JP2008531579A - Nitric oxide enhanced diuretic compounds, compositions and methods of use - Google Patents

Abstract

The present invention relates to novel compositions and kits comprising at least one nitric oxide enhancing diuretic compound, or a pharmaceutically acceptable salt thereof, and optionally at least one nitric oxide enhancing compound and / or at least one therapeutic agent. Is described. The present invention also treats (a) conditions resulting from overhydration and / or electrolyte retention; (b) treats cardiovascular disease; (c) treats renovascular disease; (d) treats diabetes (E) treat diseases resulting from oxidative stress; (f) treat endothelial dysfunction; (g) treat diseases caused by endothelial dysfunction; (h) treat cirrhosis; (j) eclampsia (K) treat osteoporosis; (l) treat nephropathy; (m) treat peripheral vascular disease; (n) treat portal hypertension; (o) central nervous system Treating a systemic disorder; (p) treating a metabolic syndrome; (q) treating a sexual dysfunction; and (r) providing a method of treating hyperlipidemia. The nitric oxide enhancing diuretic compound comprises at least one nitric oxide enhancing group attached to the diuretic compound by one or more sites such as carbon, oxygen and / or nitrogen via a non-hydrolyzable bond or moiety.

Description

FIELD OF THE INVENTION The present invention relates to a novel composition comprising at least one nitric oxide enhancing diuretic compound, or a pharmaceutically acceptable salt thereof, and optionally at least one nitric oxide enhancing compound and / or at least one therapeutic agent. Items and kits are described. The present invention also treats (a) conditions resulting from overhydration and / or electrolyte retention; (b) treats cardiovascular disease; (c) treats renovascular disease; (d) treats diabetes (E) treat diseases resulting from oxidative stress; (f) treat endothelial dysfunction; (g) treat diseases caused by endothelial dysfunction; (h) treat cirrhosis; (j) eclampsia (K) treat osteoporosis; (l) treat nephropathy; (m) treat peripheral vascular disease; (n) treat portal hypertension; (o) central nervous system Treating a systemic disorder; (p) treating a metabolic syndrome; (q) treating a sexual dysfunction; and (r) a method of treating hyperlipidemia. The nitric oxide enhancing diuretic compound comprises at least one nitric oxide enhancing group attached to the diuretic compound by one or more sites such as carbon, oxygen and / or nitrogen via a non-hydrolyzable bond or moiety.

RELATED APPLICATIONS Priority of US Patent Application No. 60 / 685,027 filed on May 26, 2005, Priority of US Patent Application No. 60 / 692,228 filed on June 21, 2005, and December 13, 2005 Priority of US Patent Application No. 60 / 749,853 filed as a supplement is claimed under 35 USC 119.

BACKGROUND OF THE INVENTION The decrease in cardiovascular morbidity and mortality in the United States over the past 30 years has been the result of significant advances in research on the mechanisms and therapeutic strategies of cardiovascular disease. The incidence and prevalence of myocardial infarction and death from myocardial infarction, as well as death from cerebrovascular disorders, decreased significantly during this period, mainly due to advances in prevention, early diagnosis and treatment of these very common diseases.

  Compounds administered for the treatment of diuresis, cardiovascular disease, and diseases resulting from oxidative and / or endothelial dysfunction often cause toxic, chronic and / or debilitating side effects. Cardiovascular compounds such as ACE inhibitors, β-adrenergic blockers, antithrombotic and vasodilatory compounds or antihyperlipidemic compounds exhibit respiratory toxicity leading to, for example, asthma and / or bronchitis. Therefore, there is a need in the art for compounds that are more effective and less toxic and that can be used at lower doses. The present invention is directed to these and other important objectives.

SUMMARY OF THE INVENTIONThe present invention includes -ONO group, -SNO group, -NNO group, -ONO ₂ group, -SNO ₂ group, -NNO ₂ group,-(N ₂ O _2- ) · M ₁ ⁺ group, heterocyclic ring. At least one nitric oxide enhancing group selected from a nitric oxide donor group and a nitroxide group of the formula, via a bond or moiety that cannot be hydrolyzed, by one or more sites such as carbon, oxygen and / or nitrogen Provided are novel nitric oxide-enhancing diuretic compounds comprising a nitric oxide enhancing group directly or indirectly attached to the compound, and pharmaceutically acceptable salts thereof. The heterocyclic nitric oxide donor is preferably furoxan, sydnonimine, oxatriazol-5-one and / or oxatriazole-5-imine. Nitric oxide enhanced diuretic compounds are not prodrugs of parental diuretic compounds. The present invention also provides compositions comprising the novel compounds described herein in a pharmaceutically acceptable carrier.

The present invention also applies to --ONO group, --SNO group, --NNO group, --ONO ₂ group, --SNO ₂ group, --NNO ₂ group,-(N ₂ O _2- ) M ₁ ⁺ group, heterocyclic At least one nitric oxide enhancing group selected from a nitric oxide donor group and a nitroxide group of the diuretic compound via one or more sites such as carbon, oxygen and / or nitrogen via a non-hydrolyzable bond or moiety Diuresis by administering at least one diuretic compound comprising a nitric oxide enhancing group directly or indirectly bound to a pharmaceutically acceptable salt thereof, and optionally at least one nitric oxide enhancing compound It is based on the discovery that the properties of the compounds are improved. Nitric oxide enhancing compounds include, for example, S-nitrosothiol, nitrite, nitrate, N-oxo-N-nitrosamine, furoxan, sydnonimine, SPM 3672, SPM 4757, SPM 5185, SPM 5186 and analogs thereof, nitric oxide synthase These are the substrates of each isozyme, as well as nitroxide. Accordingly, another aspect of the invention provides a composition comprising at least one nitric oxide enhancing diuretic compound and at least one nitric oxide enhancing compound. The present invention also provides such compositions in a pharmaceutically acceptable carrier.

The present invention relates to at least one nitric oxide enhancing diuretic compound and optionally at least one nitric oxide enhancing compound and / or aldosterone antagonist, α-adrenergic receptor antagonist, angiotensin II antagonist, angiotensin converting enzyme (ACE) inhibition. Agents, antidiabetic compounds, antihyperlipidemic compounds, antioxidants, antithrombotic and vasodilatory compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H ₂ receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, platelet reducing agents, proton pump inhibitors, renin inhibitors, selective Shikurookishige Over peptidase -2 (COX-2) inhibitors, and includes two or more combinations thereof are not limited to, to provide a containing at least one therapeutic agent composition. In one embodiment, the at least one therapeutic agent is selected from the group consisting of aldosterone antagonists, angiotensin II antagonists, angiotensin converting enzyme (ACE) inhibitors, β-adrenergic antagonists, digitalis, diuretics, and hydralazine compounds. . The present invention also provides such compositions in a pharmaceutically acceptable carrier.

  In another aspect of the invention, an effective amount of at least one nitric oxide enhancing diuretic compound and an aldosterone antagonist, an angiotensin II antagonist, an angiotensin converting enzyme (ACE) inhibitor, a β-adrenergic antagonist, a calcium channel blocker, a diuretic And a composition comprising at least one therapeutic agent selected from the group consisting of a hydralazine compound and a renin inhibitor. The present invention also provides such compositions in a pharmaceutically acceptable carrier.

The present invention provides an effective amount of at least one nitric oxide-enhancing diuretic compound and optionally, for example, an aldosterone antagonist, an α-adrenergic receptor antagonist, an angiotensin II antagonist, an angiotensin converting enzyme (ACE) inhibitor, an antidiabetic compound, Antihyperlipidemic compound, antioxidant, antithrombotic and vasodilatory compound, β-adrenergic antagonist, calcium channel blocker, digitalis, diuretic, endothelin antagonist, hydralazine compound, H ₂ receptor antagonist, medium Endopeptidase inhibitors, non-steroidal anti-inflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, thrombocytopenia, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors And these (A) treating a condition resulting from overhydration and / or electrolyte retention in a patient in need thereof, comprising administering to the patient at least one therapeutic agent, such as a combination of two or more; b) treat cardiovascular disease; (c) treat renovascular disease; (d) treat diabetes; (e) treat disease resulting from oxidative stress; (f) treat endothelial dysfunction; (g) treat diseases caused by endothelial dysfunction; (h) treat cirrhosis; (j) treat pre-eclampsia; (k) treat osteoporosis; (l) treat nephropathy; ( m) treat peripheral vascular disease; (n) treat portal hypertension; (o) treat central nervous system disorders; (p) treat metabolic syndrome; (q) treat sexual dysfunction And (r) providing a method of treating hyperlipidemia. The method can optionally further comprise administration of at least one nitric oxide enhancing compound. In this aspect of the invention, the method comprises (i) administering a nitric oxide enhanced diuretic compound, (ii) administering a nitric oxide enhanced diuretic compound and a nitric oxide enhancing compound, (iii) a nitric oxide enhanced diuretic Administering a compound and a therapeutic agent; or (iv) administering a nitric oxide enhancing diuretic compound, a nitric oxide enhancing compound and a therapeutic agent. In one embodiment, the at least one therapeutic agent is from an aldosterone antagonist, an angiotensin II antagonist, an angiotensin converting enzyme (ACE) inhibitor, a β-adrenergic antagonist, a calcium channel blocker, a diuretic, a hydralazine compound, and a renin inhibitor. Selected from the group consisting of The nitric oxide enhancing diuretic compound, nitric oxide donor, and / or therapeutic agent may be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.

Another aspect of the present invention provides a kit comprising at least one nitric oxide enhancing diuretic compound and optionally at least one nitric oxide enhancing compound. This kit includes, for example, aldosterone antagonists, α-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin converting enzyme (ACE) inhibitors, antidiabetic compounds, antihyperlipidemic compounds, antioxidants, antithrombotic and Vasodilatory compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H ₂ receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal anti-inflammatory compounds (NSAIDs) At least one, such as a phosphodiesterase inhibitor, potassium channel blocker, thrombocytopenic agent, proton pump inhibitor, renin inhibitor, selective cyclooxygenase-2 (COX-2) inhibitor, and combinations of two or more thereof Horn Ryoyaku may further include a. The nitric oxide enhancing diuretic compound, nitric oxide enhancing compound and / or therapeutic agent may be a separate component in the kit or in the form of a composition in one or more pharmaceutically acceptable carriers. Also good.

  These and other aspects of the invention are described in detail herein.

DETAILED DESCRIPTION OF THE INVENTION The following terms used throughout this disclosure should be understood to have the following meanings unless otherwise indicated.

  “States resulting from overhydration and / or electrolyte retention” include swelling of the lower limbs, fatigue, fluid retention, cardiac hypertrophy, lung edema, brain edema, at least partially heart failure, cirrhosis, poor circulation, lymphatic system disorders, chronic Nephritis, malnutrition, use of oral contraceptives, premenstrual syndrome, sunburn, hypertension, Meniere's disease, glaucoma, cystic fibrosis and / or edema related to factors selected from the group consisting of sodium and potassium imbalance However, it is not limited to these.

  `` Cardiovascular disease or disorder '' refers to any cardiovascular disease or disorder known in the art and includes heart failure, restenosis, hypertension (e.g., pulmonary hypertension, agitated hypertension, idiopathic hypertension, low renin hypertension, salinity Sensitive hypertension, low renin, salt-sensitive hypertension, thromboembolic pulmonary hypertension; pregnancy-induced hypertension; renovascular hypertension; hypertension-dependent end-stage renal failure, hypertension associated with cardiovascular surgery, left ventricular hypertension, etc.), dilated function Disorder, coronary artery disease, myocardial infarction, cerebral infarction, atherosclerosis, atherogenesis, cerebrovascular disease, angina (including chronic, stability, instability and atypical (Printz metal) angina), aneurysm , Ischemic heart disease, cerebral ischemia, myocardial ischemia, thrombosis, platelet aggregation, platelet adhesion, smooth muscle cell proliferation, vascular or non-vascular complications related to the use of medical devices, use of medical devices Consecutive wound, vascular or non-vascular wall injury, peripheral vascular disease, neointimal hyperplasia after percutaneous transluminal coronary angiography, vascular transplantation, coronary artery bypass surgery, thromboembolic event, stenosis after angioplasty, coronary artery Plaque inflammation, hypercholesterolemia, embolism, stroke, shock, arrhythmia, atrial fibrillation or atrial flutter, thrombo-occlusive and re-occlusive cerebrovascular incidents, left ventricular dysfunction and hypertrophy, etc. Although it is mentioned, it is not limited to these.

  “Heart failure” includes, but is not limited to, congestive heart failure, compensatory heart failure, decompensated heart failure, and the like.

“Thromboembolic events” include ischemic stroke, transient ischemic stroke, myocardial infarction, angina, thrombosis (eg restenosis, arterial thrombosis, coronary thrombosis, heart valve thrombosis, coronary stenosis) Thrombotic occlusion, artificial vascular thrombus, and primary and secondary thrombotic strokes), thromboembolism (e.g., pulmonary thromboembolism, cerebral thromboembolism, etc.), venous thrombosis, thrombocytopenia, hemorrhagic disease, Examples include, but are not limited to, thrombotic and reocclusions and acute vascular events. Patients at risk of developing a thromboembolic event include those with a family history or genetic predisposition to thromboembolic disease who have had ischemic stroke, transient ischemic stroke, myocardial infarction From patients with altered prostacyclin / thromboxane A ₂ homeostasis or normal thromboxane A ₂ levels, including those with stable angina or chronic stable angina, and patients with diabetes and rheumatoid arthritis And patients with an increased risk of thromboembolism.

  “Diseases resulting from oxidative stress” include, for example, atherogenesis, atherosclerosis, arteriosclerosis, atherosclerosis, hypertension-related vascular hypertrophy, hyperlipoproteinemia, normal vascular degeneration due to aging, parathyroid reaction Sexual hyperplasia, kidney disease (e.g. acute or chronic), neoplastic disease, inflammatory disease, neurological and acute bronchopulmonary disease, tumor formation, ischemia-reperfusion syndrome, arthritis, sepsis, cognitive dysfunction, endotoxin Refers to any disease that involves the generation of free radicals or radical compounds, such as shock, organ failure due to endotoxin, and the like.

  “Renovascular disease” refers to renal failure (eg, acute or chronic), renal dysfunction, nephritic edema, acute glomerulonephritis, oliguric renal failure, renal alteration related to severe hypertension, unilateral parenchyma Cellular kidney disease, polycystic kidney disease, chronic pyelonephritis, kidney disease related to renal dysfunction, complications related to dialysis or kidney transplantation, renovascular hypertension, nephropathy, glomerulonephritis, scleroderma, glomerulus Refers to any disease or dysfunction of the kidney system, including but not limited to sclerosis and the like.

  “Endothelial dysfunction” refers to disturbances of the endothelium, particularly any physiological process caused by the production of nitric oxide, regardless of the cause. This may be due to, for example, invasive techniques such as coronary responsiveness to acetylcholine or methacholine, or, for example, blood flow measurements, dilation of brachial artery flow by cuff occlusion of the upper and lower arms of the elbow, upper arm It can be assessed by noninvasive techniques such as arterial ultrasonography, imaging techniques, measurement of blood biomarkers such as asymmetric dimethylarginine (ADMA). In the latter measurement, endothelium-dependent blood flow-dependent dilation should be reduced in patients diagnosed with endothelial dysfunction.

  “Methods of treating endothelial dysfunction” include, for example, prior to the onset / diagnosis of diseases caused by or caused by endothelial dysfunction such as atherosclerosis, hypertension, diabetes, heart failure, etc. Treatment, but is not limited to.

  Examples of the “method of treating a disease caused by endothelial dysfunction” include atherosclerosis, heart failure, hypertension, cardiovascular disease, cerebrovascular disease, renovascular disease, mesenteric vascular disease, pulmonary vascular disease, Treatment of any disease resulting from endothelial failure such as, but not limited to, ocular vascular disease, peripheral vascular disease, peripheral ischemic disease and the like.

  `` Central nervous system disorder '' includes, for example, neurodegenerative disorders, cognitive or memory dysfunction, memory and learning disorders, attention disorders, Alzheimer's disease, depression, schizophrenia, memory loss, dementia, senile dementia, Any responding to positive regulation of AMPA receptors, such as learning deficits, attention deficits, cognitive deficits, mental disorders, intellectual dysfunction, autism, neurotoxic effects, alcoholism or substance abuse Examples include, but are not limited to, obstacles.

  "Metabolic syndrome", also known as "insulin resistance syndrome" or "syndrome X", is an increase in the amount of adipose tissue inside the abdominal cavity, senile diabetes, ie increased risk of developing type II diabetes A condition characterized by sex, high levels of blood lipids and high blood pressure.

  “Sexual dysfunction” refers to and includes male erectile dysfunction and female sexual dysfunction. Examples of sexual dysfunction include, but are not limited to, sexual pain, sexual desire disorder, sexual arousal, orgasmic dysfunction, sexual pain, and vaginal spasticity.

“Therapeutic agent” includes any therapeutic agent that can be used to treat or prevent the diseases described herein. Examples of `` therapeutic agents '' include aldosterone antagonists, α-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin converting enzyme (ACE) inhibitors, antidiabetic compounds, antihyperlipidemic compounds, antioxidants, Thrombotic and vasodilatory compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H ₂ receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal anti-inflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, thrombocytopenic agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and the like. Therapeutic agents include, but are not limited to, pharmaceutically acceptable salts, prodrugs thereof, and the corresponding nitrosated and / or nitrosylated and / or heterocyclic nitric oxide donor and / or nitroxide derivatives. Pharmaceutical derivatives thereof are not included. Although nitric oxide enhancing compounds have therapeutic activity, the term “therapeutic agent” does not include the nitric oxide enhancing compounds described herein, since nitric oxide enhancing compounds are separately defined.

  “Prodrug” refers to a compound that becomes more active in vivo.

  "Antioxidant" refers to and includes any compound that can react with and quench free radicals.

  An “angiotensin converting enzyme (ACE) inhibitor” refers to a compound that inhibits an enzyme that catalyzes the conversion of angiotensin I to angiotensin II. ACE inhibitors include amino acids and derivatives thereof, peptides, including dipeptides and tripeptides, and ACEs involved in the renin-angiotensin system by inhibiting the activity of ACE, thereby reducing or eliminating the formation of the pressor angiotensin II Examples include, but are not limited to, antibodies against.

  “Angiotensin II antagonist” refers to a compound that interferes with the function, synthesis or catabolism of angiotensin II. Angiotensin II antagonists include peptide compounds that include, but are not limited to, angiotensin II antagonists, angiotensin II receptor antagonists, agents that activate angiotensin II catabolism, and agents that interfere with the synthesis of angiotensin I from angiotensin II. And non-peptide compounds. The renin-angiotensin system is involved in the regulation of hemodynamics and water and electrolyte balance. Factors that reduce blood volume, renal perfusion pressure, or plasma sodium concentration tend to activate this system, while factors that increase these parameters tend to inhibit their function.

  An “antihyperlipidemic compound”, for example, lowers serum low density lipoprotein (LDL) cholesterol levels or inhibits oxidation of LDL cholesterol, but lowers high density lipoprotein (HDL) serum cholesterol levels , Refers to any compound or agent that has a beneficial modulating effect on serum cholesterol levels, which can be similarly maintained or increased. Preferably, the antihyperlipidemic compound brings the serum levels of LDL cholesterol and HDL cholesterol (more preferably, triglyceride levels) to normal or nearly normal levels.

  “Diuretic compound” refers to and includes any compound or agent that increases the amount of urine excreted from a patient.

  “Neutral endopeptidase inhibitors” refers to and includes compounds that are antagonists of the renin-angiotensin-aldosterone system, including compounds that are dual inhibitors of neutral endopeptidase and angiotensin converting (ACE) enzyme.

  A “renin inhibitor” refers to a compound that interferes with the activity of renin.

  “Phosphodiesterase inhibitor” or “PDE inhibitor” refers to any compound that inhibits the enzyme phosphodiesterase. The term refers to selective or non-selective inhibitors of cyclic guanosine 3 ′, 5′-monophosphate phosphodiesterase (cGMP-PDE) and cyclic adenosine 3 ′, 5′-monophosphate phosphodiesterase (cAMP-PDE). .

  A “thrombocytopenic agent” refers to a compound that interferes with thrombus formation via any number of possible mechanisms. Thrombocytopenic agents include, but are not limited to, fibrinolytics, anticoagulants and any inhibitor of platelet function. As an inhibitor of platelet function, the ability of mature platelets to perform their normal physiological roles (i.e., their normal functions such as adhesion to cells and non-cellular entities, aggregation, release of factors such as growth factors) Drugs that impair the process.

“Proton pump inhibitor” refers to any compound that reversibly or irreversibly blocks gastric acid secretion by inhibiting the H ⁺ / K ⁺ -ATPase enzyme system on the secretory surface of gastric wall cells.

  “NSAID” refers to a non-steroidal anti-inflammatory compound or non-steroidal anti-inflammatory agent. NSAIDs include inhibitors of various isozymes of cyclooxygenase (including but not limited to cyclooxygenase-1 and -2), and as inhibitors of both cyclooxygenase and lipoxygenase, prostaglandins and certain autocidal inhibitors Inhibits cyclooxygenase, an enzyme involved in the biosynthesis of.

“Cyclooxygenase-2 (COX-2) selective inhibitor” refers to a compound that selectively inhibits the cyclooxygenase-2 enzyme over the cyclooxygenase-1 enzyme. In one embodiment, the compounds of the invention have a cyclooxygenase-2 IC _{50 of} less than about 2 μM and a cyclooxygenase-1 IC ₅₀ of greater than about 5 μM in a human whole blood COX-2 assay (Brideau et al., Inflamm Res., 45: 68-74 (1996)), and likewise has a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 10, preferably at least 40. In another embodiment, the compounds of the invention have a cyclooxygenase-1 IC ₅₀ of greater than about 1 μM, preferably greater than 20 μM. The compounds of the present invention can also inhibit lipoxygenase enzymes. Such selectivity can indicate that the frequency of side effects induced by general NSAIDs can be reduced.

  “Patient” refers to animals, preferably mammals, most preferably humans, and includes males and females, as well as children and adults.

  “Transdermal” refers to the delivery of a compound by flowing the compound through the skin and into the bloodstream.

  “Transmucosal” refers to delivery of a compound by flowing the compound into the bloodstream through mucosal tissue.

  “Increased permeability” or “increased permeability” refers to the permeability of a selected pharmaceutically active compound to the skin or mucosal tissue such that the rate at which the compound penetrates the skin or mucosal tissue is increased. An increase.

  “Carrier” or “vehicle” refers to a carrier material suitable for administration of the compound, which is non-toxic and does not interact adversely with any component of the composition, eg, any liquid, gel, solvent Any such materials known in the art such as diluents, solubilizers and the like.

  “Sustained release” refers to the release of an active compound and / or composition such that the blood level of the active compound is maintained within a desired therapeutic range over a period of time. Sustained release formulations can be prepared using any conventional method known to those skilled in the art to obtain the desired release characteristics.

  “Nitric oxide enhancement” refers to compounds and functional groups that can increase endogenous nitric oxide under physiological conditions. Nitric oxide enhancing compounds include, but are not limited to, nitric oxide releasing compounds, nitric oxide donating compounds, nitric oxide donors, radical scavenging compounds and / or reactive oxygen species scavenger compounds. In one embodiment, the radical scavenging compound comprises a nitroxide group.

  A “nitroxide group” is the ability to mimic superoxide dismutase and catalase and act as a radical scavenger or to react with superoxide or other reactive oxygen species via a stable aminoxyl radical, ie N-oxide The compound which has this.

“Nitric oxide adducts” or “NO adducts” are the three redox forms of nitric oxide under physiological conditions so that the biological activity of the nitric oxide species is expressed at the intended site of action. A compound and functional group that can donate, release, and / or directly or indirectly transfer any of (NO ⁺ , NO ⁻ , NO ·).

“Nitric oxide release” or “nitrogen oxide donation” refers to the three redox forms of nitric oxide (NO ⁺ , NO ⁻ , NO, A method of donating, releasing, and / or transferring directly or indirectly any of NO.).

  “Nitric oxide donor” or “NO donor” refers to donor, release, and / or direct or indirect transfer of nitric oxide species and / or nitric oxide or endothelium-derived relaxing factor (EDRF). Stimulates endogenous production in vivo and / or increases endogenous levels of nitric oxide or EDRF in vivo and / or oxidizes to produce nitric oxide and / or is a substrate for nitric oxide synthase, And / or a compound that is cytochrome P450. “NO donors” also include compounds that are precursors of L-arginine, inhibitors of the arginase enzyme, and nitric oxide mediators.

  “Heterocyclic nitric oxide donor” refers to a trisubstituted 5-membered ring containing 2 or 3 nitrogen atoms and at least one oxygen atom. Heterocyclic nitric oxide donors can donate and / or release nitric oxide species by heterocycle decomposition. Exemplary heterocyclic nitric oxide donors include oxatriazol-5-one, oxatriazole-5-imine, sydnonimine, furoxan and the like.

  “Alkyl” is a lower alkyl group, substituted lower alkyl group, haloalkyl group, hydroxyalkyl group, alkenyl group, substituted alkenyl group, alkynyl group, bridged cycloalkyl group, cycloalkyl group, or Heterocycle. An alkyl group may also include one or more radical species, such as, for example, a cycloalkylalkyl group or a heterocyclic alkyl group.

  `` Lower alkyl '' refers to a branched or straight chain non-chain containing 1 to about 10 carbon atoms (preferably 1 to about 8 carbon atoms, more preferably 1 to about 6 carbon atoms). It refers to a cyclic alkyl group. Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl and the like.

“Substituted lower alkyl” refers to a lower alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with one or more R ¹⁰⁰ groups, wherein each R ¹⁰⁰ is Independently, a hydroxy, ester, amidyl, oxo, carboxyl, carboxamide, halo, cyano, nitrate, nitrite, thionitrate, thionitrite or amino group as defined herein.

  “Haloalkyl” means a lower alkyl group, alkenyl group, alkynyl group, bridged cycloalkyl group, cycloalkyl group, or cycloalkyl group, as defined herein, to which is appended one or more halogens, as defined herein, or Heterocycle. Exemplary haloalkyl groups include trifluoromethyl, chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and the like.

“Alkenyl” refers to branched or straight chain C ₂ -C ₁₀ hydrocarbons (preferably C _{2 to} C ₈ hydrocarbons, more preferably C ₂₎ that may contain one or more carbon-carbon double bonds. It refers to -C ₆ hydrocarbons). Exemplary alkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexane-1-yl, heptene- Examples include 1-yl and octen-1-yl.

“Lower alkenyl” refers to a branched or straight chain C ₂ -C ₄ hydrocarbon that may contain one or two carbon-carbon double bonds.

“Substituted alkenyl” refers to a branched or straight chain that may contain one or more carbon-carbon double bonds, wherein one or more hydrogen atoms are replaced with one or more R ¹⁰⁰ groups C ₂ -C ₁₀ hydrocarbon (preferably a C ₂ -C ₈ hydrocarbon, more preferably a C ₂ -C ₆ hydrocarbon) refers to, wherein each R ¹⁰⁰ is independently as defined herein A hydroxy, oxo, carboxyl, carboxamide, halo, cyano or amino group.

The term "alkynyl", one or more carbon - may include carbon triple bond unsaturation acyclic C ₂ -C ₁₀ hydrocarbon (preferably a C ₂ -C ₈ hydrocarbon, more preferably C ₂ -C ₆ Hydrocarbon). Exemplary alkynyl include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl -2-yl, hexyl-3-yl, 3,3-dimethyl-butyn-1-yl, and the like.

  “Bridged cycloalkyl” refers to two or more cycloalkyl groups, heterocyclic groups, or combinations thereof fused via adjacent or non-adjacent atoms. Bridged cycloalkyl groups are independent of alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkyl carboxylic acid, aryl, amidyl, ester, alkyl carboxylic acid ester, carboxamide, alkyl carboxamide, oxo and nitro. May be substituted or unsubstituted with one, two or three selected substituents. Exemplary bridged cycloalkyl groups include adamantyl, decahydronaphthyl, quinuclidyl, 2,6-dioxabicyclo (3.3.0) octane, 7-oxabicyclo (2.2.1) heptyl, 8-azabicyclo (3,2, 1) Oct-2-enyl and the like can be mentioned.

  “Cycloalkyl” refers to a saturated or unsaturated cyclic hydrocarbon containing from about 3 to about 10 carbon atoms. Cycloalkyl groups are alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, aryl, amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylic acid ester, carboxamide, It may be substituted or unsubstituted with one, two, or three substituents independently selected from alkylcarboxamide, oxo, alkylsulfinyl, and nitro. Exemplary cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like.

  “Heterocycle or heterocyclic group” means about 2 to about 10 carbon atoms in which 1 to about 4 carbon atoms are replaced with one or more nitrogen, oxygen, and / or sulfur atoms. A saturated or unsaturated cyclic hydrocarbon group having (preferably about 4 to about 6 carbon atoms). Sulfur may be in the thio, sulfinyl, or sulfonyl oxidation state. The heterocyclic ring or heterocyclic group may be fused with an aromatic hydrocarbon group. Heterocyclic groups are alkyl, alkoxy, amino, alkylthio, aryloxy, arylthio, arylalkyl, hydroxy, oxo, thiar, halo, carboxyl, carboxylic acid ester, alkylcarboxylic acid, alkylcarboxylic acid ester, aryl, arylcarboxylic acid, One independently selected from aryl carboxylic acid ester, amidyl, ester, alkylcarbonyl, arylcarbonyl, alkylsulfinyl, carboxamide, alkylcarboxamide, arylcarboxamide, sulfonic acid, sulfonic acid ester, sulfonamidonitrate, and nitro, It may be substituted or unsubstituted with 2 or 3 substituents. Exemplary heterocyclic groups include pyrrolyl, furyl, thienyl, 3-pyrrolinyl, 4,5,6-trihydro-2H-pyranyl, pyridinyl, 1,4-dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, Oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrahydrofuranyl, tetrazolyl, pyrrolinyl, pyrrolindinyl, oxazolidinyl 1,3-dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5- Triazinyl, 1,3,5-tri Examples include thianyl, benzo (b) thiophenyl, benzoimidazolyl, benzothiazolinyl, quinolinyl, 2,6-dioxabicyclo (3.3.0) octane.

  “Heterocyclic compound” refers to monocyclic and polycyclic compounds containing at least one aryl or heterocycle.

  “Aryl” refers to a monocyclic, bicyclic, carbocyclic or heterocyclic ring system comprising one or two aromatic rings. Exemplary aryl groups include phenyl, pyridyl, naphthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like. Aryl groups (including bicyclic aryl groups), alkyl, alkoxy, alkylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, halo, cyano, alkylsulfinyl, hydroxy, carboxyl, carboxylic acid Ester, alkyl carboxylic acid, alkyl carboxylic acid ester, aryl, aryl carboxylic acid, aryl carboxylic acid ester, alkyl carbonyl, aryl carbonyl, amidyl, ester, carboxamide, alkyl carboxamide, carbonyl, sulfonic acid, sulfonic acid ester, sulfonamide, and It may be substituted or unsubstituted with one, two, or three substituents independently selected from nitro. Exemplary substituted aryl groups include tetrafluorophenyl, pentafluorophenyl, sulfonamido, alkylsulfonyl, arylsulfonyl and the like.

The term "cycloalkenyl", one or more carbon - may include carbon double bond unsaturated cyclic C ₂ -C ₁₀ hydrocarbon (preferably a C ₂ -C ₈ hydrocarbon, more preferably C ₂ -C ₆ hydrocarbon).

  “Alkylaryl” refers to an alkyl group, as defined herein, to which is appended an aryl group, as defined herein. Exemplary alkylaryl groups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl and the like.

  “Arylalkyl” refers to an aryl group, as defined herein, attached to an alkyl group, as defined herein. Exemplary arylalkyl groups include benzyl, phenylethyl, 4-hydroxybenzyl, 3-fluorobenzyl, 2-fluorophenylethyl and the like.

  “Arylalkenyl” refers to an aryl group, as defined herein, attached to an alkenyl group, as defined herein. Exemplary arylalkenyl groups include styryl, propenylphenyl, and the like.

  “Cycloalkylalkyl” refers to a cycloalkyl group, as defined herein, attached to an alkyl group, as defined herein.

  “Cycloalkylalkoxy” refers to a cycloalkyl group, as defined herein, attached to an alkoxy, as defined herein.

  “Cycloalkylalkylthio” refers to a cycloalkyl group, as defined herein, attached to an alkylthio, as defined herein.

  “Heterocyclic alkyl” refers to a heterocyclic group, as defined herein, attached to an alkyl group, as defined herein.

  “Aryl heterocycle” means a heterocycle as defined herein in which a bicyclic or tricyclic ring consisting of an aryl ring as defined herein is attached via two adjacent carbon atoms of the aryl ring. The one added to Exemplary aryl heterocycles include dihydroindole, 1,2,3,4-tetra-hydroquinoline, and the like.

  “Alkylheterocycle” refers to an alkyl group as defined herein bonded to a heterocycle group as defined herein. Exemplary alkyl heterocycles include 2-pyridylmethyl, 1-methylpiperidin-2-one-3-methyl, and the like.

“Alkoxy” refers to R ₅₀ O—, wherein R ₅₀ is an alkyl group as defined herein (preferably a lower alkyl group or a haloalkyl group as defined herein). Exemplary alkoxy groups include methoxy, ethoxy, t-butoxy, cyclopentyloxy, trifluoromethoxy and the like.

“Aryloxy” refers to R ₅₅ O—, wherein R ₅₅ is an aryl group, as defined herein. Exemplary aryloxy groups include naphthyloxy, quinolyloxy, isoquinolidinyloxy, and the like.

“Alkylthio” refers to R ₅₀ S—, wherein R ₅₀ is an alkyl group, as defined herein.

  “Lower alkylthio” refers to a lower alkyl group, as defined herein, appended to a thio group, as defined herein.

  “Arylalkoxy” or “alkoxyaryl” refers to an alkoxy group, as defined herein, appended with an aryl group, as defined herein. Exemplary arylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy, and the like.

  “Arylalkylthio” refers to an alkylthio group, as defined herein, appended with an aryl group, as defined herein. Exemplary arylalkylthio groups include benzylthio, phenylethylthio, chlorophenylethylthio, and the like.

  “Arylalkylthioalkyl” refers to an arylalkylthio group, as defined herein, to which is appended an alkyl group, as defined herein. Exemplary arylalkylthioalkyl groups include benzylthiomethyl, phenylethylthiomethyl, chlorophenylethylthioethyl, and the like.

  “Alkylthioalkyl” refers to an alkylthio group, as defined herein, to which is appended an alkyl group, as defined herein. Exemplary alkylthioalkyl groups include allylthiomethyl, ethylthiomethyl, trifluoroethylthioethyl, and the like.

  “Alkoxyalkyl” refers to an alkoxy group, as defined herein, appended to an alkyl group, as defined herein. Exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, isopropoxymethyl, and the like.

  “Alkoxyhaloalkyl” refers to an alkoxy group, as defined herein, appended to a haloalkyl group, as defined herein. Exemplary alkoxyhaloalkyl groups include 4-methoxy-2-chlorobutyl and the like.

“Cycloalkoxy” refers to R ₅₄ O—, wherein R ₅₄ is a cycloalkyl group or a bridged cycloalkyl group, as defined herein. Exemplary cycloalkoxy groups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

“Cycloalkylthio” refers to R ₅₄ S—, wherein R ₅₄ is a cycloalkyl group or a bridged cycloalkyl group, as defined herein. Exemplary cycloalkylthio groups include cyclopropylthio, cyclopentylthio, cyclohexylthio, and the like.

  “Haloalkoxy” refers to an alkoxy group, as defined herein, in which one or more of the hydrogen atoms of the alkoxy group has been replaced with a halogen, as defined herein. Exemplary haloalkoxy groups include 1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.

  “Hydroxy” refers to —OH.

  “Oxy” refers to —O—.

  “Oxo” refers to ═O.

“Oxylate” refers to —O ⁻ R ₇₇ ⁺ , where R ₇₇ is an organic or inorganic cation.

  “Thiol” refers to —SH.

  “Thio” refers to —S—.

"Oxime" refers to = N-OR ₈₁ , wherein R ₈₁ is hydrogen, alkyl group, aryl group, alkylsulfonyl group, arylsulfonyl group, carboxylic acid ester, alkylcarbonyl group, arylcarbonyl group, carboxamide group , An alkoxyalkyl group or an alkoxyaryl group.

The term "hydrazone", = 'refers to _(81, wherein _{R NN (R 81) R)} ' 81 are independently selected from R _81, R ₈₁ are as defined herein.

“Hydrazino” refers to H ₂ NN (H) —.

  “Organic cation” refers to a positively charged organic ion. Exemplary organic cations include alkyl substituted ammonium cations and the like.

  “Inorganic cation” refers to a positively charged metal ion. Exemplary inorganic cations include group I metal cations such as sodium, potassium, magnesium, calcium, and the like.

  “Hydroxyalkyl” refers to a hydroxy group, as defined herein, appended to an alkyl group, as defined herein.

“Nitrate” refers to —O—NO ₂ , ie, nitric oxide.

  “Nitrite” refers to —O—NO, ie, nitric oxide.

“Thionitrate” refers to —S—NO ₂ .

  “Thionitrite” and “nitrosothiol” refer to —S—NO.

“Nitro” refers to the group —NO ₂ and “nitrosated” refers to compounds that are substituted therewith.

  “Nitroso” refers to the —NO group and “nitrosylation” refers to compounds that are substituted therewith.

  “Nitrile” and “cyano” refer to —CN.

  “Halogen” or “halo” refers to iodine (I), bromine (Br), chlorine (Cl), and / or fluorine (F).

“Imine” refers to —C (═NR ₅₁ ) —, wherein R ₅₁ represents a hydrogen atom, an alkyl group, an aryl group, or an aryl heterocycle as defined herein.

  “Amine” refers to any organic compound containing at least one basic nitrogen atom.

“Amino” refers to —NH ₂ , alkylamino group, dialkylamino group, arylamino group, diarylamino group, alkylarylamino group or heterocycle as defined herein.

“Alkylamino” refers to R ₅₀ NH—, wherein R ₅₀ is an alkyl group, as defined herein. Exemplary alkylamino groups include methylamino, ethylamino, butylamino, cyclohexylamino, and the like.

“Arylamino” refers to R ₅₅ NH—, wherein R ₅₅ is an aryl group, as defined herein.

“Dialkylamino” refers to R ₅₂ R ₅₃ N—, wherein R ₅₂ and R ₅₃ are each independently an alkyl group, as defined herein. Exemplary dialkylamino groups include dimethylamino, diethylamino, methylpropargylamino, and the like.

“Diarylamino” refers to R ₅₅ R ₆₀ N—, wherein R ₅₅ and R ₆₀ are each independently an aryl group, as defined herein.

“Alkylarylamino” or “arylalkylamino” refers to R ₅₂ R ₅₅ N—, wherein R ₅₂ is an alkyl group, as defined herein, and R ₅₅ is as defined herein. An aryl group.

“Alkylarylalkylamino” refers to R ₅₂ R ₇₉ N—, wherein R ₅₂ is an alkyl group, as defined herein, and R ₇₉ is an arylalkyl group, as defined herein. It is.

“Alkylcycloalkylamino” refers to R ₅₂ R ₈₀ N—, wherein R ₅₂ is an alkyl group, as defined herein, and R ₈₀ is a cycloalkyl group, as defined herein. It is.

  “Aminoalkyl” means an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group as defined herein, to which is added an alkyl group as defined herein. A group or heterocycle. Exemplary aminoalkyl groups include dimethylaminopropyl, diphenylaminocyclopentyl, methylaminomethyl, and the like.

  “Aminoaryl” refers to an aryl group to which an alkylamino group, an arylamino group or an arylalkylamino group has been added. Exemplary aminoaryl groups include anilino, N-methylanilino, N-benzylanilino, and the like.

  “Sulfinyl” refers to —S (O) —.

  “Methothial” refers to —C (S) —.

  “Chial” means = S.

“Sulfonyl” refers to —S (O) ₂ ^— .

“Sulfonic acid” refers to —S (O) ₂ OR ₇₆ , wherein R ₇₆ is hydrogen, an organic cation or an inorganic cation as defined herein.

  “Alkylsulfonic acid” refers to a sulfonic acid group, as defined herein, appended to an alkyl group, as defined herein.

  “Arylsulfonic acid” refers to a sulfonic acid group, as defined herein, appended to an aryl group, as defined herein.

“Sulfonic acid ester” refers to —S (O) ₂ OR ₅₈ , wherein R ₅₈ is an alkyl group, an aryl group, or an aryl heterocycle as defined herein.

“Sulfonamido” refers to —S (O) ₂ —N (R ₅₁ ) (R ₅₇ ), wherein R ₅₁ and R ₅₇ are each independently a hydrogen atom, alkyl as defined herein A group, an aryl group or an aryl heterocycle, or R ₅₁ and R _{57 taken} together are a heterocycle, a cycloalkyl group or a bridged cycloalkyl group as defined herein.

  “Alkylsulfonamido” refers to a sulfonamido group, as defined herein, appended to an alkyl group, as defined herein.

  “Arylsulfonamido” refers to a sulfonamido group, as defined herein, appended to an aryl group, as defined herein.

“Alkylthio” refers to R ₅₀ S—, wherein R ₅₀ is an alkyl group as defined herein (preferably a lower alkyl group as defined herein).

“Arylthio” refers to R ₅₅ S—, wherein R ₅₅ is an aryl group, as defined herein.

  “Arylalkylthio” refers to an aryl group, as defined herein, appended to an alkylthio group, as defined herein.

“Alkylsulfinyl” refers to R ₅₀ —S (O) —, wherein R ₅₀ is an alkyl group, as defined herein.

“Alkylsulfonyl” refers to R ₅₀ —S (O) ₂ —, wherein R ₅₀ is an alkyl group, as defined herein.

“Alkylsulfonyloxy” refers to R ₅₀ —S (O) ₂ —O—, wherein R ₅₀ is an alkyl group, as defined herein.

“Arylsulfinyl” refers to R ₅₅ —S (O) —, wherein R ₅₅ is an aryl group, as defined herein.

“Arylsulfonyl” refers to R ₅₅ —S (O) ₂ —, wherein R ₅₅ is an aryl group, as defined herein.

“Arylsulfonyloxy” refers to R ₅₅ —S (O) ₂ —O—, wherein R ₅₅ is an aryl group, as defined herein.

“Amidyl” refers to R ₅₁ C (O) N (R ₅₇ ) —, wherein R ₅₁ and R ₅₇ are each independently a hydrogen atom, alkyl group, aryl group or An aryl heterocycle.

“Ester” refers to R ₅₁ C (O) R ₈₂ —, wherein R ₅₁ is a hydrogen atom, an alkyl group, an aryl group or an aryl heterocyclic ring as defined herein, and R ₈₂ is an oxygen atom. Or sulfur.

“Carbamoyl” refers to —OC (O) N (R ₅₁ ) (R ₅₇ ), in which R ₅₁ and R ₅₇ each independently represent a hydrogen atom, an alkyl group, or an aryl as defined herein. A group or an aryl heterocycle, or R ₅₁ and R _{57 taken} together are a heterocycle, a cycloalkyl group or a bridged cycloalkyl group as defined herein.

“Carboxyl” refers to —C (O) OR ₇₆ , wherein R ₇₆ is a hydrogen, an organic cation or an inorganic cation as defined herein.

  “Carbonyl” refers to —C (O) —.

“Alkylcarbonyl” refers to R ₅₂ —C (O) —, wherein R ₅₂ is an alkyl group, as defined herein.

“Arylcarbonyl” refers to R ₅₅ —C (O) —, wherein R ₅₅ is an aryl group, as defined herein.

“Arylalkylcarbonyl” refers to R ₅₅ —R ₅₂ —C (O) —, wherein R ₅₅ is an aryl group, as defined herein, and R ₅₂ , as defined herein. An alkyl group.

“Alkylarylcarbonyl” refers to R ₅₂ —R ₅₅ —C (O) —, wherein R ₅₅ is an aryl group, as defined herein, and R ₅₂ , as defined herein. An alkyl group.

“Heterocyclic alkylcarbonyl” refers to R ₇₈ C (O) —, wherein R ₇₈ is a heterocyclic alkyl group, as defined herein.

“Carboxylic acid ester” refers to —C (O) OR ₅₈ , wherein R ₅₈ is an alkyl group, an aryl group, or an aryl heterocycle as defined herein.

  “Alkylcarboxylic acid” and “alkylcarboxyl” refer to an alkyl group, as defined herein, appended to a carboxyl group, as defined herein.

  “Alkylcarboxylic ester” refers to an alkyl group, as defined herein, appended to a carboxylic ester group, as defined herein.

  “Alkyl ester” refers to an alkyl group, as defined herein, appended to an ester group, as defined herein.

  “Arylcarboxylic acid” refers to an aryl group, as defined herein, appended to a carboxyl group, as defined herein.

  “Arylcarboxylic ester” and “arylcarboxyl” refer to an aryl group, as defined herein, appended to a carboxylic ester group, as defined herein.

  “Aryl ester” refers to an aryl group, as defined herein, appended to an ester group, as defined herein.

“Carboxamide” refers to —C (O) N (R ₅₁ ) (R ₅₇ ), wherein R ₅₁ and R ₅₇ are each independently a hydrogen atom, an alkyl group, or an aryl as defined herein. A group or an aryl heterocycle, or R ₅₁ and R _{57 taken} together are a heterocycle, a cycloalkyl group or a bridged cycloalkyl as defined herein.

  “Alkylcarboxamide” refers to an alkyl group, as defined herein, appended to a carboxamide group, as defined herein.

  “Arylcarboxamide” refers to an aryl group, as defined herein, appended to a carboxamide group, as defined herein.

`` Urea '' refers to -N (R ₅₉ ) -C (O) N (R ₅₁ ) (R ₅₇ ), wherein R ₅₁ , R ₅₇ , and R ₅₉ are each independently Is a hydrogen atom, an alkyl group, an aryl group or an aryl heterocycle as defined, or R ₅₁ and R ₅₇ together are a heterocycle, a cycloalkyl group or a bridged cycloalkyl group as defined herein. is there.

“Phosphoryl” refers to —P (R ₇₀ ) (R ₇₁ ) (R ₇₂ ), wherein R ₇₀ is a lone pair, thial or oxo, and R ₇₁ and R ₇₂ are each independently A covalent bond as defined herein, hydrogen, lower alkyl, alkoxy, alkylamino, hydroxy, oxy or aryl.

“Phosphoric acid” refers to —P (O) (OR ₅₁ ) OH, wherein R ₅₁ is a hydrogen atom, an alkyl group, an aryl group or an aryl heterocycle as defined herein.

“Phosphonic acid” refers to —P (O) (R ₅₁ ) OH, wherein R ₅₁ is a hydrogen atom, an alkyl group, an aryl group or an aryl heterocycle as defined herein.

“Sily” refers to —Si (R ₇₃ ) (R ₇₄ ) (R ₇₅ ), wherein R ₇₃ , R ₇₄ and R ₇₅ are each independently a covalent bond, lower alkyl, as defined herein. , Alkoxy, aryl or arylalkoxy.

  The compounds and compositions of the present invention are thiazides (e.g., althiazide, bendroflumethiazide, benzchlortriazide, benzhydrochlorothiazide, benzthiazide, butiazide, chlorothiazide, cyclopentethiazide, cyclothiazide, epithiazide, ethiazide, Hydrobenzthiazide, hydrochlorothiazide, hydroflumethiazide, methylclothiazide, methylcyclothiazide, penflutazide, polythiazide, tecrotiazide, trichlormethiazide, triflumetazide etc.); allylcem, ambuside, amiloride, aminomethrazine, Azosemide, bemetizide, bumetanide, butazolamide, butizide, canrenone, carperitide, chloraminophenamide, chlorazanil, chlormello Phosphorus, chlorthalidone, cicletanide, clofenamide, clopamide, chlorexolone, conivaptan, daglutril, dichlorophenamide, disulfamide, ethacrynic acid, etoxzolamide, etzoline, phenoldopam, fenxone, furosemide, mepridemide, mebutizide Sodium, mercumallylic acid, mersalyl, metazolamide, methiclan, metolazone, mozabaptan, muzolimine, N- (5-1,3,4-thiadiazol-2-yl) acetamide, nesiritide, pamabrom, paraflutidide, piretanide, proteobromine (protheobromine), kinetazone, scoparius, spironolactone, theobromine, ticlinaphene, torsemide, tolvaptan, triamterene, Including trypamide, uralitide, xypamide, potassium, AT 189000, AY 31906, BG 9928, BG 9791, C 2921, DTI 0017, JDL 961, KW 3902, MCC 134, SLV 306, SR 121463, WAY 140288, ZP 120 etc. A diuretic, not limited to these. Diuretic compounds contemplated are Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, (1996); Merck Index on CD-ROM, 13th edition; STN Express, file phar and file registry Are described in more detail in the literature, the disclosure of each of which is hereby incorporated by reference in its entirety.

In one embodiment, the diuretic compound of the present invention has an -ONO group, -SNO group, -NNO group, -ONO ₂ group, -SNO ₂ group, -NNO ₂ group,-(N ₂ O _2- ) · M ₁ ^At least one nitric oxide enhancing group selected from the group consisting of a ⁺ group, a heterocyclic group (e.g., furoxan, sydnonimine, oxatriazol-5-one, oxatriazole-5-imine) and a nitroxide group, It contains a nitric oxide (NO) enhancing group that is linked directly or indirectly to the diuretic compound through one or more sites such as carbon, oxygen and / or nitrogen by an incapable bond or moiety. The nitric oxide enhanced diuretic compound can be represented by the formula (A).
(Diuretic compound)-(Nonhydrolyzable bond)-(Linking group) _aa- (NO enhancing group) (A)
here:
The diuretic compound can be any known in the art. In one embodiment, the diuretic compound is althiazide, bendroflumethiazide, benzthiazide, butiazide, chlorothiazide, cyclothiazide, ethiazide, fenxone, hydrochlorothiazide, hydroflumethiazide, methiclotiazide, metolazone, paraflutide, polythiazide, kinetazone, tecrothiad, Trichlormethiazide;
Nitric oxide enhancing groups are -ONO, -SNO, -NNO, -ONO ₂ , -SNO ₂ , -NNO ₂ ,-(N ₂ O _2- ) M ₁ ⁺ , heterocyclic groups ( Selected from the group consisting of, for example, furoxan, sydnonimine, oxatriazol-5-one, oxatriazole-5-imine) and nitroxide groups;
aa is O or 1;
when aa is 0, the nitric oxide enhancing group is directly linked to the angiotensin II antagonist compound via a non-hydrolyzable bond;
When aa is 1, the linking group can be any known in the art;
The linking group may optionally include one or more hydrolyzable bonds, but the hydrolyzable bond may not be directly adjacent to the diuretic compound. In other words, at least one atom or moiety in the linking group directly adjacent to the diuretic compound must form a non-hydrolyzable bond with the diuretic compound.

式中:
X₂は-C(O)-または-S(O)₂であり;
Y₂は塩素またはCF₃であり;
-V₂-U₂-W₂-は以下であり:
(i) -NH-(C(R_q)(R_r))-NR_q-; または
(ii) -NH-C(R_q)=N-;
R_qおよびR_rは各出現時において独立して水素、低級アルキル基、置換アルキル基、ベンジル基、アリール基、アルキルアリール基、-CH₂-S-CH-CH=CH₂; -CH₂-S-CF₃、-CH₂-S-CH₂-C₆H₅またはK'であり;
K'は-G-E_c-(C(R_e)(R_f))_x-W_d-(C(R_e)(R_f))_y-W_i-E_j-W_g-(C(R_e)(R_f))_z-V₄であり;
Kは-(W)_a-E_b-(C(R_e)(R_f))_p1-E_c-(C(R_e)(R_f))_x-(W)_d-(C(R_e)(R_f))_y-(W)_i-E_j-(W)_g-(C(R_e)(R_f))_z-V₄であり;
a、b、c、d、g、iおよびjはそれぞれ独立して0から3の整数であり;
p₁、x、yおよびzはそれぞれ独立して0から10の整数であり;
Gは複素環、-CH₂、酸素または窒素であり;
V₄はV₃、R_e、-U₃-V₅またはV₆であり;
V₃は以下であり:

R₂₄は-C₆H₄R₂₉、-CN、-S(O)₂-C₆H₄R₂₉、-C(O)-N(R_a)(R_i)、-NO₂、-C(O)-OR₂₅または-S(O)₂-R₂₅であり;
R₂₅はアリール基、低級アルキル基、ハロアルキル基、ヒドロキシアルキル基またはアリールアルキル基であり;
R₂₆は-C(O)-または-S(O)₂-であり;
R₂₉は水素、-CN、-S(O)₂-R₂₅、-C(O)-N(R_a)(R_i)、-NO₂または-C(O)-OR₂₅であり;
T'は酸素、硫黄またはNR₆であり;
R₆は水素、低級アルキル基、またはアリール基であり;
V₆は以下であり:

Z₅は-CH₂または酸素であり;
Z₆は-CHまたは窒素であり;
k₁は1から3の整数であり;
Wは各出現時において独立して-C(O)-、-C(S)-、-T₃-、-(C(R_e)(R_f))_h-、-N(R_a)R_i、アルキル基、アリール基、複素環、アリール複素環、-(CH₂CH₂O)_q1-または複素環式の酸化窒素供与体であり;
Eは各出現時において独立して-T₃-、アルキル基、アリール基、-(C(R_e)(R_f))_h-、複素環、アリール複素環、-(CH₂CH₂O)_ql-またはY₄であり;
Y₄は以下であり:

Tは-S(O)_o-; カルボニルまたは共有結合であり;
oは0から2の整数であり;
R_jおよびR_kは独立してアルキル基、アリール基から選択され、または結合している窒素原子と一緒になったR_jおよびR_kは複素環であり;
T₃は各出現時において独立して共有結合、カルボニル、酸素、-S(O)_o-または-N(R_a)R_iであり;
hは1から10の整数であり;
q₁は1から5の整数であり;
R_eおよびR_fはそれぞれ独立して水素、アルキル、シクロアルコキシ、ハロゲン、ヒドロキシ、ヒドロキシアルキル、アルコキシアルキル、アリール複素環、アルキルアリール、アルキルシクロアルキル、アルキル複素環、シクロアルキルアルキル、シクロアルキルチオ、アリールアルキルチオ、アリールアルキルチオアルキル、アルキルチオアルキル、シクロアルケニル、複素環アルキル、アルコキシ、ハロアルコキシ、アミノ、アルキルアミノ、ジアルキルアミノ、アリールアミノ、ジアリールアミノ、アルキルアリールアミノ、アルコキシハロアルキル、スルホン酸、スルホン酸エステル、アルキルスルホン酸、アリールスルホン酸、アリールアルコキシ、アルキルチオ、アリールチオ、シアノ、アミノアルキル、アミノアリール、アリール、アリールアルキル、アルキルアリール、カルボキサミド、アルキルカルボキサミド、アリールカルボキサミド、アミジル、カルボキシル、カルバモイル、アルキルカルボン酸、アリールカルボン酸、アルキルカルボニル、アリールカルボニル、エステル、カルボン酸エステル、アルキルカルボン酸エステル、アリールカルボン酸エステル、スルホンアミド、アルキルスルホンアミド、アリールスルホンアミド、アルキルスルホニル、アルキルスルホニルオキシ、アリールスルホニル、アリールスルホニルオキシ、スルホン酸エステル、アルキルエステル、アリールエステル、尿素、ホスホリル、ニトロ、-U₃-V₅、V₆、-(C(R_o)(R_p))_k1-U₃-V₅、-(C(R_o)(R_p))_k1-U₃-V₃、-(C(R_o)(R_p))_k1-U₃-V₆、-(C(R_o)(R_p))_k1-U₃-C(O)-V₆であり、または結合している炭素と一緒になったR_eおよびR_fはカルボニル、メタンチアル、複素環、シクロアルキル基、アリール基、オキシム、イミン、ヒドラゾン、架橋シクロアルキル基、

を形成し;
R_OおよびR_Pはそれぞれ独立して水素、アルキル、シクロアルコキシ、ハロゲン、ヒドロキシ、ヒドロキシアルキル、アルコキシアルキル、アリール複素環、アルキルアリール、アルキルシクロアルキル、アルキル複素環、シクロアルキルアルキル、シクロアルキルチオ、アリールアルキルチオ、アリールアルキルチオアルキル、アルキルチオアルキル、シクロアルケニル、複素環アルキル、アルコキシ、ハロアルコキシ、アミノ、アルキルアミノ、ジアルキルアミノ、アリールアミノ、ジアリールアミノ、アルキルアリールアミノ、アルコキシハロアルキル、スルホン酸、スルホン酸エステル、アルキルスルホン酸、アリールスルホン酸、アリールアルコキシ、アルキルチオ、アリールチオ、シアノ、アミノアルキル、アミノアリール、アリール、アリールアルキル、アルキルアリール、カルボキサミド、アルキルカルボキサミド、アリールカルボキサミド、アミジル、カルボキシル、カルバモイル、アルキルカルボン酸、アリールカルボン酸、アルキルカルボニル、アリールカルボニル、エステル、カルボン酸エステル、アルキルカルボン酸エステル、アリールカルボン酸エステル、スルホンアミド、アルキルスルホンアミド、アリールスルホンアミド、アルキルスルホニル、アルキルスルホニルオキシ、アリールスルホニル、アリールスルホニルオキシ、スルホン酸エステル、アルキルエステル、アリールエステル、尿素、ホスホリル、ニトロ、-U₃-V₅、V₆であり、または結合している炭素と一緒になったR_OおよびR_Pはカルボニル、メタンチアル、複素環、シクロアルキル基、アリール基、オキシム、イミン、ヒドラゾン、架橋シクロアルキル基、

を形成し;
U₃は酸素、硫黄または-N(R_a)R_iであり;
V₅は-NOまたは-NO₂ (すなわち酸化窒素)であり;
k_lは1から3の整数であり;
R_aは孤立電子対、水素またはアルキル基であり;
R_iは水素、アルキル、アリール、アルキルカルボン酸、アリールカルボン酸、アルキルカルボン酸エステル、アリールカルボン酸エステル、アルキルカルボキサミド、アリールカルボキサミド、アルキルアリール、アルキルスルフィニル、アルキルスルホニル、アルキルスルホニルオキシ、アリールスルフィニル、アリールスルホニル、アリールスルホニルオキシ、スルホンアミド、カルボキサミド、カルボン酸エステル、アミノアルキル、アミノアリール、-CH₂-C-(U₃-V₅)(R_e)(R_f)、隣接原子との結合であってその原子に二重結合をもたらす結合またはM₁ ⁺が有機もしくは無機陽イオンである-(N₂O₂-)・M₁ ⁺であり; ならびに
但し式(I)の化合物は、-ONO基、-SNO基、-NNO基、-ONO₂基、-SNO₂基、-NNO₂基、-(N₂O₂-)・M₁ ⁺基、複素環式の酸化窒素供与体基およびニトロキシド基から選択される少なくとも1つの酸化窒素増強基であって、加水分解できない結合または部分を経て炭素、酸素および/または窒素などの1つまたは複数の部位により利尿化合物に結び付けられた酸化窒素増強基を含まなければならないという条件である。 In another aspect, the present invention describes nitric oxide enhanced diuretic compounds of formula (I) and pharmaceutically acceptable salts thereof.

Where:
X ₂ is -C (O)-or -S (O) ₂ ;
Y ₂ is chlorine or CF ₃ ;
-V ₂ -U ₂ -W _2- is:
(i) -NH- (C (R _q ) (R _r ))-NR _q- ; or
(ii) -NH-C (R _q ) = N-;
R _q and R _r each independently represent hydrogen, a lower alkyl group, a substituted alkyl group, a benzyl group, an aryl group, an alkylaryl group, —CH ₂ —S—CH—CH═CH ₂ ; —CH ₂ — S-CF ₃ , -CH ₂ -S-CH ₂ -C ₆ H ₅ or K ';
K 'is -GE _c- (C (R _e ) (R _f )) _x -W _d- (C (R _e ) (R _f )) _y -W _i -E _j -W _g- (C (R _e ) (R _f )) _z -V ₄ ;
K is-(W) _a -E _b- (C (R _e ) (R _f )) _p1 -E _c- (C (R _e ) (R _f )) _x- (W) _d- (C (R _e ) (R _f )) _y- (W) _i -E _j- (W) _g- (C (R _e ) (R _f )) _z -V ₄ ;
a, b, c, d, g, i and j are each independently an integer from 0 to 3;
p ₁ , x, y and z are each independently an integer from 0 to 10;
G is heterocyclic, -CH _2, oxygen or nitrogen;
V ₄ is V ₃ , _Re , -U ₃ -V ₅ or V ₆ ;
V ₃ is:

R ₂₄ is -C ₆ H ₄ R ₂₉ , -CN, -S (O) ₂ -C ₆ H ₄ R ₂₉ , -C (O) -N (R _a ) (R _i ), -NO ₂ , -C (O) -OR ₂₅ or -S (O) ₂ -R ₂₅ ;
R ₂₅ is an aryl group, a lower alkyl group, a haloalkyl group, a hydroxyalkyl group or an arylalkyl group;
R ₂₆ is -C (O)-or -S (O) _2- ;
R ₂₉ is hydrogen, -CN, -S (O) ₂ -R ₂₅ , -C (O) -N (R _a ) (R _i ), -NO ₂ or -C (O) -OR ₂₅ ;
T ′ is oxygen, sulfur or NR ₆ ;
R ₆ is hydrogen, a lower alkyl group, or an aryl group;
V ₆ is:

Z ₅ is -CH ₂ or oxygen;
Z ₆ is -CH or nitrogen;
k ₁ is an integer from 1 to 3;
W is independently at each occurrence -C (O)-, -C (S)-, -T ₃ -,-(C (R _e) (R _f )) _h- , -N (R _a ) R _i, alkyl group, aryl group, heterocyclic, aryl _{heterocyclic, - (CH 2 CH 2 O} ) q1 - or be a heterocyclic nitric oxide donor;
E is independently at each occurrence -T _3- , alkyl group, aryl group,-(C (R _e ) (R _f )) _h- , heterocycle, arylheterocycle,-(CH ₂ CH ₂ O) _ql -or Y ₄ ;
Y ₄ is:

T is -S (O) _o- ; carbonyl or a covalent bond;
o is an integer from 0 to 2;
R _j and R _k are independently selected from alkyl groups, aryl groups, or R _j and R _k together with the nitrogen atom to which they are attached are heterocycles;
T ₃ is independently a covalent bond, carbonyl, oxygen, -S (O) _o -or -N (R _a ) R _i at each occurrence;
h is an integer from 1 to 10;
q ₁ is an integer from 1 to 5;
R _e and R _f are each independently hydrogen, alkyl, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, arylheterocycle, alkylaryl, alkylcycloalkyl, alkylheterocycle, cycloalkylalkyl, cycloalkylthio, aryl Alkylthio, arylalkylthioalkyl, alkylthioalkyl, cycloalkenyl, heterocyclic alkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, sulfonic acid, sulfonate ester, alkyl Sulfonic acid, arylsulfonic acid, arylalkoxy, alkylthio, arylthio, cyano, aminoalkyl, aminoaryl, ali , Arylalkyl, alkylaryl, carboxamide, alkylcarboxamide, arylcarboxamide, amidyl, carboxyl, carbamoyl, alkylcarboxylic acid, arylcarboxylic acid, alkylcarbonyl, arylcarbonyl, ester, carboxylic acid ester, alkylcarboxylic acid ester, arylcarboxylic acid Ester, sulfonamide, alkylsulfonamide, arylsulfonamide, alkylsulfonyl, alkylsulfonyloxy, arylsulfonyl, arylsulfonyloxy, sulfonic acid ester, alkyl ester, aryl ester, urea, phosphoryl, nitro, -U ₃ -V ₅ , V ₆ ,-(C (R _o ) (R _p )) _k1 -U ₃ -V ₅ ,-(C (R _o ) (R _p )) _k1 -U ₃ -V ₃ ,-(C (R _o ) _{(R p)) k1 -U 3} -V 6, - (C (R o) (R p)) is a _{k1 -U 3 -C (O) -V} 6, or binding To the R _e and R _f taken together with the carbon and carbonyl, Methanthial, heterocycle, cycloalkyl group, aryl group, oxime, imine, hydrazone, a bridged cycloalkyl group,

Forming;
R _O and R _P are each independently hydrogen, alkyl, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, arylheterocycle, alkylaryl, alkylcycloalkyl, alkylheterocycle, cycloalkylalkyl, cycloalkylthio, aryl Alkylthio, arylalkylthioalkyl, alkylthioalkyl, cycloalkenyl, heterocyclic alkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, sulfonic acid, sulfonate ester, alkyl Sulfonic acid, arylsulfonic acid, arylalkoxy, alkylthio, arylthio, cyano, aminoalkyl, aminoaryl, ali , Arylalkyl, alkylaryl, carboxamide, alkylcarboxamide, arylcarboxamide, amidyl, carboxyl, carbamoyl, alkylcarboxylic acid, arylcarboxylic acid, alkylcarbonyl, arylcarbonyl, ester, carboxylic acid ester, alkylcarboxylic acid ester, arylcarboxylic acid Ester, sulfonamide, alkylsulfonamide, arylsulfonamide, alkylsulfonyl, alkylsulfonyloxy, arylsulfonyl, arylsulfonyloxy, sulfonic acid ester, alkyl ester, aryl ester, urea, phosphoryl, nitro, -U ₃ -V ₅ , a V _6, or a bond to R _O and R _P taken together with the carbon and carbonyl, Methanthial, heterocycle, cycloalkyl group, Aryl group, oxime, imine, hydrazone, a bridged cycloalkyl group,

Forming;
U ₃ is oxygen, sulfur or -N (R _a ) R _i ;
V ₅ is -NO or -NO ₂ (i.e. nitric oxide);
k _l is an integer from 1 to 3;
R _a is a lone pair, hydrogen or an alkyl group;
_Ri is hydrogen, alkyl, aryl, alkyl carboxylic acid, aryl carboxylic acid, alkyl carboxylic acid ester, aryl carboxylic acid ester, alkyl carboxamide, aryl carboxamide, alkyl aryl, alkyl sulfinyl, alkyl sulfonyl, alkyl sulfonyloxy, aryl sulfinyl, aryl sulfonyl, arylsulfonyloxy, sulfonamido, carboxamido, carboxylic acid esters, aminoalkyl, _{aminoaryl, -CH 2 -C- (U 3 -V} 5) (R e) (R f), there a bond with an adjacent atom A bond that provides a double bond to the atom or M ₁ ⁺ is an organic or inorganic cation-(N ₂ O _2- ) · M ₁ ⁺ ; and the compound of formula (I) is an -ONO group , -SnO group, -nno group, -ONO ₂ group, -SnO ₂ group, -nno _{2 group, - (N 2 O 2 -} ) · M 1 + group, nitric oxide donating heterocyclic Oxidation linked to a diuretic compound by one or more sites such as carbon, oxygen and / or nitrogen via a bond or moiety that cannot be hydrolyzed, at least one nitric oxide enhancing group selected from a group and a nitroxide group The condition is that a nitrogen enhancing group must be included.

When the meaning of a large number of variables present in an array is selected as `` covalent bond '' or when the selected integer is 0, the intent is to share one radical with another radical It shows a bond. For example, E ₀ means a covalent bond, E ₂ means (EE), (C (R ₄ ) (R ₄ )) ₂ means -C (R ₄ ) (R ₄ ) -C (R ₄ ) (R ₄ )-.

  In another aspect of the invention, the compound of formula (I) is a nitric oxide enhanced althiazide, nitric oxide enhanced bendroflumethiazide, nitric oxide enhanced benzthiazide, nitric oxide enhanced butiazide, nitric oxide enhanced chlorothiazide, nitric oxide enhanced cyclohexane. Thiazide, nitric oxide-enhanced ethiazide, nitric oxide-enhanced fenxone, nitric oxide-enhanced hydrochlorothiazide, nitric oxide-enhanced hydroflumethiazide, nitric oxide-enhanced metichlothiazide, nitric oxide-enhanced metolazone, nitric oxide-enhanced paraflutidide, nitric oxide-enhanced polythiazide, nitric oxide-enhanced kinetazone, Nitric oxide-enhanced teclothiazide, nitric oxide-enhanced trichlormethiazide; and pharmaceutically acceptable salts thereof.

Y₂は塩素またはCF₃であり;
x₁は1から6の整数であり;
y₁は0から3の整数であり;
R₃₀は水素、低級アルキル基、-(CH₂)_x1-O-NO₂であり; および
R₃₁は水素または低級アルキル基である。 In another aspect of the invention, the compound of formula (I) is a compound of formula (II) to formula (XXVII), or a pharmaceutically acceptable salt thereof,
Compounds of formula (II) to formula (XXVII) are:

Y ₂ is chlorine or CF ₃ ;
x ₁ is an integer from 1 to 6;
y ₁ is an integer from 0 to 3;
R ₃₀ is hydrogen, a lower alkyl group, — (CH ₂ ) _x1 —O—NO ₂ ; and
R ₃₁ is hydrogen or a lower alkyl group.

In another embodiment, the nitric oxide enhanced hydrochlorothiazide of formula (I) is:
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [5- (nitrooxy) pentyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- [3,4-bis (nitrooxy) butyl] -6-chloro-3,4-dihydro-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [3- (nitrooxy) propyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- (4-methyl-5-oxide-1,2,5-oxadiazole-3 -Yl)-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide, (3R)- ;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide, (3S)- ;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6-chloro-1 '-[5- (nitrooxy) -1-oxopentyl] -, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[4,5-bis (nitrooxy) -1-oxopentyl]- 6-chloro-, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6-chloro-1 '-[2-methyl-3- (nitrooxy) -2 -[(Nitrooxy) methyl] -1-oxopropyl]-, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6-chloro-1 '-[3-[(nitrooxy) methyl] benzoyl]- , 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6-chloro-1 '-[6- (nitrooxy) -1-oxohexyl] -, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-2-acetic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, (2R) -2,3-bis (nitrooxy) propyl ester, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2-[[3-[(nitrooxy) methyl] phenyl] methyl]-, 1,1- Dioxide;
2H-1,2,4-Benzothiadiazine-2-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N- [3- (nitrooxy) propyl]-, 1,1- Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [3- (nitrooxy) propyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[[4- [2- (nitrooxy) ethyl] -1-piperidinyl] methyl]- , 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[[4- [2- (nitrooxy) ethyl] -1-piperidinyl] methyl]- , 1,1-dioxide, 2-hydroxy-1,2,3-propanetricarboxylate (1: 1) (salt);
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2-[(4-methyl-5-oxide-1,2,5-oxadiazole- 3-yl) methyl]-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-2-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N-methyl-N- [2- (nitrooxy) ethyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-2-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N, N-bis [2- (nitrooxy) ethyl]-, 1 , 1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [4- (nitrooxy) butyl]-, 1,1-dioxide;
Pentanoic acid, 4,5-bis (nitrooxy)-, 2- [7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadia Gin-2-yl] ethyl ester;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [4,5-bis (nitrooxy) pentyl] -6-chloro-3,4-dihydro-, 1,1-dioxide;
Pentanoic acid, 5- (nitrooxy)-, 2- [7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazine-2 -Yl] ethyl ester;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[[methyl [2- (nitrooxy) ethyl] amino] methyl]-, 1,1 -Dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [5- (nitrooxy) pentyl]-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [6- (nitrooxy) hexyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[(3S) -3,4-bis (nitrooxy) butyl] -6-chloro-3,4-dihydro-, 1,1 -Dioxide;
2H-1,2,4-Benzothiadiazine-3-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N, N-bis [2- (nitrooxy) ethyl]-, 1 , 1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- [3,5-bis [(nitrooxy) methyl] phenyl] -6-chloro-3,4-dihydro-, 1,1- Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [2- (nitrooxy) ethyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-4-nitro-2- [2- (nitrooxy) ethyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) -3,3-bis [(nitrooxy) methyl] butyl] -, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [5- (nitrooxy) -4,4-bis [(nitrooxy) methyl] pentyl] -, 1,1-dioxide;
Acetamide, N-[[7- (Aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] methyl] -2 -[Bis [2- (nitrooxy) ethyl] amino]-;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [6- (nitrooxy) hexyl]-, 1,1-dioxide;
Acetamide, N-[[7- (Aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] methyl] -2 -[Bis [2- (nitrooxy) ethyl] amino] -N-methyl-;
(5-{[{[7- (Aminosulfonyl) -6-chloro-1,1-dioxide-3,4-dihydro-2H-1,2,4-benzothiadiazin-3-yl] methyl} ( Methyl) amino] carbonyl} -1,3-phenylene) bis (methylene) dinitrate;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2-[(2E) -4- (nitrooxy) -2-butenyl], 1,1- Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[[3- (4-Bromobutoxy) -5-[(nitrooxy) methyl] phenyl] methyl] -6-chloro-3, 4-dihydro-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [4- [3,5-bis [(nitrooxy) methyl] phenoxy] butyl] -6-chloro-3,4-dihydro- , 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [3- [3,5-bis [(nitrooxy) methyl] phenoxy] propyl] -6-chloro-3,4-dihydro- , 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [2- [3,5-bis [(nitrooxy) methyl] phenoxy] ethyl] -6-chloro-3,4-dihydro- , 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-2-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N, N-bis [3- (nitrooxy) propyl]-, 1 , 1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[(3R) -3,4-bis (nitrooxy) butyl] -6-chloro-3,4-dihydro-, 1,1 -Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [2- (nitrooxy) ethyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[(2R) -2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-, 1,1 -Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[(2S) -2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-, 1,1 -Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-4-nitro-, 1,1 -Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [2-hydroxy-3- (nitrooxy) propyl] -4-nitro-, 1, 1-dioxide;
1-piperidinyloxy, 4-[[7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl ] Methyl] -2,2,6,6-tetramethyl-;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl ) Methyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- [2- [3,5-bis [(nitrooxy) methyl] phenyl] ethyl] -6-chloro-3,4-dihydro- , 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-4-methyl-3- [4- (nitrooxy) butyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3-[(1R) -1,2-bis (nitrooxy) ethyl] -6-chloro-3,4-dihydro-4-methyl- , 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3-[(1S) -1,2-bis (nitrooxy) ethyl] -6-chloro-3,4-dihydro-4-methyl- , 1,1-dioxide;
1-pyrrolidinyloxy, 3- [7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] -2,2,5,5-tetramethyl-;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -1'-yloxy, 7- (aminosulfonyl) -6-chloro-2 ', 2', 6 ' , 6'-tetramethyl-1,1-dioxide-;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [3- (nitrooxy) -2-[(nitrooxy) methyl] propyl]-, 1 , 1-dioxide;
And pharmaceutically acceptable salts thereof.

In another embodiment, the nitric oxide enhanced hydroflumethiazide of formula (I) is:
2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- [5- (nitrooxy) pentyl] -6- (trifluoromethyl)-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- [3- (nitrooxy) propyl] -6- (trifluoromethyl)-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- [3,4-bis (nitrooxy) butyl] -3,4-dihydro-6- (trifluoromethyl)-, 1,1 -Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- (4-methyl-5-oxide-1,2,5-oxadiazol-3-yl)- 6- (trifluoromethyl)-, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[5- (nitrooxy) -1-oxopentyl] -6- ( (Trifluoromethyl)-, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[3-[(nitrooxy) methyl] benzoyl] -6- (tri Fluoromethyl)-, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[2-methyl-3- (nitrooxy) -2-[(nitrooxy ) Methyl] -1-oxopropyl] -6- (trifluoromethyl)-, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[2,2-dimethyl-3- (nitrooxy) -1-oxo Propyl] -6- (trifluoromethyl)-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 3- [3,5-bis [(nitrooxy) methyl] phenyl] -3,4-dihydro-6- (trifluoromethyl)-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- [4- (nitrooxy) butyl] -6- (trifluoromethyl)-, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[6 (nitrooxy) -1-oxohexyl] -6- (tri Fluoromethyl)-, 1,1-dioxide; and pharmaceutically acceptable salts thereof.

In another embodiment, the nitric oxide enhanced chlorothiazide of formula (I) is:
Pentanamide, N- [7- (aminosulfonyl) -6-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] -5- (nitrooxy)-;
Hexanamide, N- [7- (aminosulfonyl) -6-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] -6- (nitrooxy)-;
4H-1,2,4-Benzothiadiazine-3-butanamide, 7- (aminosulfonyl) -N-[(2R) -2,3-bis (nitrooxy) propyl] -6-chloro-, 1,1 -Dioxide;
4H-1,2,4-Benzothiadiazine-3-propanamide, 7- (aminosulfonyl) -6-chloro-N- [2- [2- (nitrooxy) ethoxy] ethyl]-, 1,1- Dioxide;
4H-1,2,4-benzothiadiazine-3-butanamide, 7- (aminosulfonyl) -6-chloro-N- [2- (nitrooxy) ethyl]-, 1,1-dioxide;
4H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3- [5- (nitrooxy) pentyl]-, 1,1-dioxide;
4H-1,2,4-Benzothiadiazine-3-butanamide, 7- (aminosulfonyl) -N-[(2S) -2,3-bis (nitrooxy) propyl] -6-chloro-, 1,1 -Dioxide;
4H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide;
N- (5-chloro-2,4-disulfamoylphenyl) -2- {4-[(nitrooxy) methyl] phenyl} acetamide;
4H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3-[[4-[(nitrooxy) methyl] phenyl] methyl]-, 1,1-dioxide; and pharmaceutically Its acceptable salt.

In another embodiment, the nitric oxide enhanced hydrochlorothiazide of formula (I) is:
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [2- (nitrooxy) ethyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[(2R) -2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-, 1,1 -Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[(2S) -2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-, 1,1 -Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide, (3R)- ;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide, (3S)- And pharmaceutically acceptable salts thereof.

  Compounds of the present invention having one or more asymmetric carbon atoms may be optically pure enantiomers, pure diastereoisomers, mixtures of enantiomers, mixtures of diastereoisomers, enantiomeric It may exist as a racemic mixture, a racemate of diastereoisomers or a mixture of racemates of diastereoisomers. The present invention contemplates all such isomers and mixtures thereof and should be understood to be within the scope of the present invention.

In another aspect of the invention, nitric oxide enhanced diuretic compounds and pharmaceutically acceptable metabolites thereof are described. These metabolites include, but are not limited to, nitric oxide-enhancing diuretic compounds and pharmaceutically acceptable degradation products, hydrolysates, gluconoride adducts thereof, and the like. As metabolites of nitric oxide-enhanced diuretic compounds,
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- (5-hydroxypentyl)-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- (5-hydroxypentyl) -6- (trifluoromethyl)-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- (4-hydroxybutyl)-, 1,1-dioxide;
Pentanamide, N- [2,4-bis (aminosulfonyl) -5-chlorophenyl] -5- (nitrooxy)-;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- (2-hydroxyethyl)-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-2-acetic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, ethyl ester, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- (4-hydroxybutyl)-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-3-acetic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, methyl ester, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-3-acetic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-2-butanoic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 3- (aminomethyl) -6-chloro-3,4-dihydro-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- (3-hydroxypropyl)-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- (5-hydroxypentyl)-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- (4-hydroxybutyl) -6- (trifluoromethyl)-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[(methylamino) methyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- (6-hydroxyhexyl)-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [4- [3,5-bis (hydroxymethyl) phenoxy] butyl] -6-chloro-3,4-dihydro-, 1 , 1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [3- [3,5-bis (hydroxymethyl) phenoxy] propyl] -6-chloro-3,4-dihydro-, 1 , 1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [2- [3,5-bis (hydroxymethyl) phenoxy] ethyl] -6-chloro-3,4-dihydro-, 1 , 1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-2- (2,3-dihydroxypropyl) -3,4-dihydro-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [2-hydroxy-1- (hydroxymethyl) ethyl]-, 1,1-dioxide ;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- [2- [3,5-bis (hydroxymethyl) phenyl] ethyl] -6-chloro-3,4-dihydro-, 1 , 1-dioxide;
And pharmaceutically acceptable salts thereof, but are not limited thereto.

  In another aspect of the present invention, methods for producing the novel compounds of the present invention and intermediates useful in such methods are provided. The reaction is carried out in a solvent suitable for the reagent and the materials used are suitable for the conversion to take place. It will be appreciated by those skilled in the art of organic synthesis that the functionality present in the molecule must be consistent with the proposed chemical transformation. This may require judgment by the experimenter regarding the order of the synthetic steps, the necessary protecting groups and deprotection conditions. Although the starting material substituents may be incompatible with some of the required reaction conditions for some of the methods described, other methods and substituents compatible with the reaction conditions will be readily apparent to those skilled in the art. It seems to be. The use of sulfur and oxygen protecting groups is well known for protecting thiol and alcohol groups from undesired reactions during synthetic procedures, and many such protecting groups are known, such as Greene and Wuts , Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).

  The chemical reactions described herein are generally disclosed in terms of their broadest use for the preparation of the compounds of the invention. In some cases, the reaction may not be applied as described for each compound included within the disclosed scope. Those skilled in the art will readily recognize compounds where this occurs. In all such cases, the reaction may be altered by conventional modifications known to those skilled in the art, for example, by changing the reaction conditions to normal, such as by appropriate protection of interfering groups, or by changing to another conventional reagent. It is contemplated that other reactions or other conventional reactions disclosed herein can be applied to the preparation of the corresponding compounds of the present invention. In all preparation methods, all starting materials are known or are readily prepared from known starting materials.

  One skilled in the art can synthesize compounds of formula (I) according to the methods and examples described herein. Some of the parental diuretic compounds (ie diuretic compounds that do not contain nitric oxide enhancing groups) are commercially available. Similarly, syntheses of parental diuretic compounds are disclosed in, for example, U.S. Pat.Nos. 2,809,194, 2,976,289, 3,055,904, 3,058,882, 3,255,241, 3,360,518, 3,392,168, 3,565,911. No. 3,665,002, No. 3,758,506, No. 3,806,534, No. 4,010,273, No. 4,018,020, No. 6,767,917 and JP 7305,585, and German Patent No. 1,163,332, and J. Am. Chem. Soc. 82: 1132 (1960), the disclosure of each of which is incorporated herein by reference in its entirety. Utilizing conventional methods known to those skilled in the art, the parent diuretic compound is substituted to include a nitric oxide enhancing group linked to the diuretic compound via one or more sites such as carbon and / or nitrogen. Known methods for attaching heterocyclic nitric oxide donor groups to compounds include WO 99/64417, WO 94/01422, EP 0 574 726 A1, EP 0 683. 159 A1, and J. Med. Chem., 47: 2688-2693 (2004); J. Med. Chem., 47: 1840-1846 (2004); J. Med. Chem., 46: 3762-3765 (2003); J. Med. Chem., 46: 747-754 (2003); Chem Rev., 102: 1091-1134 (2002); J. Med. Chem., 42: 1941-1950 (1999); J Med. Chem., 41: 5393-5401 (1998); J. Med. Chem., 38: 4944-4949 (1995); Arzneim. Forsch. Drug Res., 47 (II): 847-854 (1997) The disclosures of each of which are incorporated herein by reference in their entirety. Those skilled in the art will be able to generate heterocyclic nitric oxide donors for the compounds described in these references to produce any of the diuretic compounds containing the heterocyclic nitric oxide donor groups described herein. The method of linking groups can be adapted.

  Known methods for attaching nitroxide groups to compounds are described in U.S. Patent Nos. 6,448,267, 6,455,542, 6,759,430, and in International Publication Nos. 2004/050084, 03/088961. Each of which is hereby incorporated by reference in its entirety.

Nitric oxide enhancement including at least one -ONO group, -SNO group, -NNO group, -ONO ₂ group, -SNO ₂ group, -NNO ₂ group and / or-(N ₂ O _2- ) · M ₁ ⁺ group Diuretic compounds can be synthesized using conventional methods known to those skilled in the art. Known methods for bonding -ONO, -SNO, -NNO, -ONO ₂ , -SNO ₂ , -NNO ₂ and / or-(N ₂ O _2- ). M ₁ ⁺ groups to compounds In U.S. Pat.Nos. 5,380,758, 5,859,053, 5,703,073, and 6,297,260; No., International Publication No. 95/09831, International Publication No. 95/19952, International Publication No. 95/30641, International Publication No. 97/27749, International Publication No.98 / 09948, International Publication No. 98/19672, International Publication No.98 / 21193, International Publication No.00 / 51988, International Publication No.00 / 61604, International Publication No.00 / 72838, International Publication No.01 / 00563 International Publication No. 01/04082, International Publication No. 01/10814, International Publication No. 01/12584, International Publication No. 01/45703, International Publication No. 00/61541, International Publication No. 00/61537, WO 02/1 1707, WO 02/30866 and Oae et al, Org. Prep. Proc. Int., 15 (3): 165-198 (1983), each of which is disclosed in its The entirety of which is incorporated herein by reference. The person skilled in the art describes in these documents: -ONO group, -SNO group, -NNO group, -ONO ₂ group, -SNO ₂ group, -NNO ₂ group and / or-(N ₂ O _2- ) The method of attaching the M ₁ ⁺ group to the compound can be applied to produce any of the nitric oxide enhanced diuretic compounds described herein.

Compounds contemplated for use in the present invention, for example, -ONO group, -SNO group, -NNO group, -ONO ₂ group, -SNO ₂ group, -NNO ₂ group,-(N ₂ O _2- ) · M ₁ ⁺ group, and at least one nitric oxide enhancing group selected from nitric oxide donor group and nitroxide radicals of heterocyclic carbon via a bond or a moiety not be hydrolyzed, oxygen, nitrogen and / or such as sulfur A nitric oxide-enhancing diuretic compound comprising a nitric oxide enhancing group linked directly or indirectly to an angiotensin II antagonist compound by one or more sites optionally releases nitric oxide or endogenous levels of nitric oxide Or otherwise deliver or transfer the biologically active form of nitric oxide directly or indirectly to the site of its intended activity, such as on the cell membrane in vivo Used in combination with compounds May be.

Nitric oxide can exist in three forms: NO- (nitroxyl), NO · (nitrogen oxide) and NO ⁺ (nitrosonium). NO. Is a highly reactive, short-lived species that can be harmful to cells. This has significant implications. This is because the pharmacological effect of NO depends on the form in which it is delivered. In contrast to the nitric oxide radical (NO.), Nitrosonium (NO ⁺ ) does not react with O ₂ or O ₂ ^- species, and the functionality that can transfer and / or release NO ⁺ and NO- is similar, Resistant to degradation in the presence of numerous redox metals. As a result, administration of charged NO equivalents (positive and / or negative) does not result in the generation of harmful byproducts or removal of active NO groups.

The term "nitrogen oxide" refers to uncharged nitric oxide (NO.) And charged nitric oxide species, preferably charged nitric oxide species such as nitrosonium ions (NO ⁺ ) and nitroxyl ions (NO-) Is included. The reactive form of nitric oxide can be provided by gaseous nitric oxide. A compound that releases, delivers or transfers nitric oxide has the structure F-NO, where F is a group that releases, delivers or transfers nitric oxide, and the compound has its intended purpose. Any and all such compounds that donate nitric oxide to their intended site of action in active form are included.

  The term “NO adduct” includes, for example, S-nitrosothiol, nitrite, nitrate, S-nitrothiol, sydnonimine, 2-hydroxy-2-nitrosohydrazine, NONOate, (E) -alkyl-2- ((E) -Hydroxyimino) -5-nitro-3-hexenamide (FK-409), (E) -alkyl-2-((E) -hydroxyimino) -5-nitro-3-hexenamine, N -((2Z, 3E) -4-ethyl-2- (hydroxyimino) -6-methyl-5-nitro-3-heptenyl) -3-pyridinecarboxamide (FR 146801), N-nitrosamine, N-hydroxylnitrosamine ( N-hydroxyl nitrosamines), nitrosimines, diazetine dioxide, oxatriazole 5-imine, oxime, hydroxylamine, N-hydroxyguanidine, hydroxyurea, benzofuroxan, furoxan and nitric oxide substrates. Including nitric oxide Any compound that releases, delivers or transfers the element is included.

  Suitable NONOates include (Z) -1- (N-methyl-N- (6- (N-methyl-ammoniohexyl) amino)) diazen-1-ium-1,2-diolate (`` MAHMA / NO ''), (Z) -1- (N- (3-ammoniopropyl) -N- (n-propyl) amino) diazen-1-ium-1,2-diolate (`` PAPA / NO ''), ( Z) -1- (N- (3-aminopropyl) -N- (4- (3-aminopropylammonio) butyl) -amino) diazen-1-ium-1,2-diolate (spermine NONOate or `` SPER / NO '') and (Z) -1- (N, N-diethylamino) diazenium-1,2-diolate sodium (diethylamine NONOate or "DEA / NO") and derivatives thereof, including but not limited to It will never be done. NONOate is also described in US Pat. Nos. 6,232,336, 5,910,316, and 5,650,447, the disclosure of which is hereby incorporated by reference in its entirety. “NO adducts” are mononitrosylated, polynitrosylated, mononitrosated and / or various naturally sensitive or artificially donated binding sites for biologically active forms of nitric oxide. Or it can be polynitrosated.

  Suitable furoxans include, but are not limited to, CAS 1609, C93-4759, C92-4678, S35b, CHF 2206, CHF 2363, and the like.

  Suitable sydnonimines include molsidomine (N-ethoxycarbonyl-3-morpholinoside nonimine), SIN-1 (3-morpholinoside nonimine) CAS936 (3- (cis-2,6-dimethylpiperidino) -N -(4-methoxybenzoyl) -sidnonimine, pyrsidomine), C87-3754 (3- (cis-2,6-dimethylpiperidino) sidnonimine, linsidomine, C4144 (3- (3,3-dimethyl-1,4 hydrochloride) -Thiazan-4-yl) side nonimine), C89-4095 (including 3- (3,3-dimethyl-1,1-dioxo-1,4-thiazan-4-yl) side nonimine hydrochloride) It will never be done.

  Suitable oximes include, but are not limited to NOR-1, NOR-3, NOR-4 and the like.

  One group of NO adducts are S-nitrosothiols, which are compounds containing at least one -S-NO group. These compounds are S-nitroso-polypeptides (the term `` polypeptide '' includes proteins and polyamino acids that do not possess a confirmed biological function, and derivatives thereof), S-nitrosylated amino acids (natural amino acids) And synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof), S-nitrosylated sugars, modified or unmodified S-nitrosylated oligonucleotides (preferably at least 5, and more preferably 5 to (200 nucleotides), linear or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted S-nitrosylated hydrocarbons, and S-nitroso heterocyclic compounds. S-nitrosothiols and methods for their preparation are described in U.S. Patent Nos. 5,380,758 and 5,703,073, WO 97/27749, WO 98/19672, and Oae et al., Org. Prep. Proc. Int., 15 (3): 165-198 (1983), the disclosure of each of which is incorporated herein by reference in its entirety.

  Another embodiment of the present invention is an S-nitroso amino acid in which the nitroso group is bonded to the sulfur group of the sulfur-containing amino acid or derivative thereof. Such compounds include, for example, S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso- Glutathione, S-nitroso-cysteinyl-glycine and the like are included.

  Among the suitable S-nitrosylated proteins are tissue type plasminogen activator (TPA) and enzymes such as cathepsin B, transport proteins such as lipoproteins, heme proteins such as hemoglobin and serum albumin, and immunoglobulins, antibodies and cytokines There are thiol-containing proteins from various functional classes, including biological defense proteins such as where the NO group is attached to one or more sulfur groups of an amino acid or amino acid derivative thereof. Such nitrosylated proteins are described in WO 93/09806, the disclosure of which is hereby incorporated by reference in its entirety. Examples include polynitrosylated albumin in which one or more thiols or other nucleophilic centers in the protein are modified.

を形成し;
R_OおよびR_Pはそれぞれ独立して水素、アルキル、シクロアルコキシ、ハロゲン、ヒドロキシ、ヒドロキシアルキル、アルコキシアルキル、アリール複素環、アルキルアリール、アルキルシクロアルキル、アルキル複素環、シクロアルキルアルキル、シクロアルキルチオ、アリールアルキルチオ、アリールアルキルチオアルキル、アルキルチオアルキル、シクロアルケニル、複素環アルキル、アルコキシ、ハロアルコキシ、アミノ、アルキルアミノ、ジアルキルアミノ、アリールアミノ、ジアリールアミノ、アルキルアリールアミノ、アルコキシハロアルキル、スルホン酸、スルホン酸エステル、アルキルスルホン酸、アリールスルホン酸、アリールアルコキシ、アルキルチオ、アリールチオ、シアノ、アミノアルキル、アミノアリール、アリール、アリールアルキル、アルキルアリール、カルボキサミド、アルキルカルボキサミド、アリールカルボキサミド、アミジル、カルボキシル、カルバモイル、アルキルカルボン酸、アリールカルボン酸、アルキルカルボニル、アリールカルボニル、エステル、カルボン酸エステル、アルキルカルボン酸エステル、アリールカルボン酸エステル、スルホンアミド、アルキルスルホンアミド、アリールスルホンアミド、アルキルスルホニル、アルキルスルホニルオキシ、アリールスルホニル、アリールスルホニルオキシ、スルホン酸エステル、アルキルエステル、アリールエステル、尿素、ホスホリル、ニトロ、-U₃-V₅、V₆であり、または結合している炭素と一緒になったR_OおよびR_Pはカルボニル、メタンチアル、複素環、シクロアルキル基、アリール基、オキシム、イミン、ヒドラゾン、架橋シクロアルキル基、

を形成し;
Z₅は-CH₂または酸素であり;
Z₆は-CHまたは窒素であり;
U₃は酸素、硫黄または-N(R_a)R_iであり;
V₅は-NOまたは-NO₂ (すなわち、酸化窒素)であり;
k_lは1から3の整数であり;
R_aは孤立電子対、水素またはアルキル基であり;
R_iは水素、アルキル、アリール、アルキルカルボン酸、アリールカルボン酸、アルキルカルボン酸エステル、アリールカルボン酸エステル、アルキルカルボキサミド、アリールカルボキサミド、アルキルアリール、アルキルスルフィニル、アルキルスルホニル、アルキルスルホニルオキシ、アリールスルフィニル、アリールスルホニル、アリールスルホニルオキシ、スルホンアミド、カルボキサミド、カルボン酸エステル、アミノアルキル、アミノアリール、-CH₂-C-(U₃-V₅)(R_e)(R_f)、隣接原子との結合であってその原子に二重結合をもたらす結合またはM₁ ⁺が有機もしくは無機陽イオンである-(N₂O₂-)・M₁ ⁺であり; ならびに
V₃およびV₆は本明細書において規定されるとおりである。 Other examples of suitable S-nitrosothiols include the following.
(i) HS (C (R _e ) (R _f )) _m SNO;
(ii) ONS (C (R _e ) (R _f )) _m R _e ; or
(iii) H ₂ N-CH (CO ₂ H)-(CH ₂ ) _m -C (O) NH-CH (CH ₂ SNO) -C (O) NH-CH ₂ -CO ₂ H;
Where m is an integer from 2 to 20;
R _e and R _f are each independently hydrogen, alkyl, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, arylheterocycle, alkylaryl, alkylcycloalkyl, alkylheterocycle, cycloalkylalkyl, cycloalkylthio, aryl Alkylthio, arylalkylthioalkyl, alkylthioalkyl, cycloalkenyl, heterocyclic alkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, sulfonic acid, sulfonate ester, alkyl Sulfonic acid, arylsulfonic acid, arylalkoxy, alkylthio, arylthio, cyano, aminoalkyl, aminoaryl, ali , Arylalkyl, alkylaryl, carboxamide, alkylcarboxamide, arylcarboxamide, amidyl, carboxyl, carbamoyl, alkylcarboxylic acid, arylcarboxylic acid, alkylcarbonyl, arylcarbonyl, ester, carboxylic acid ester, alkylcarboxylic acid ester, arylcarboxylic acid Ester, sulfonamide, alkylsulfonamide, arylsulfonamide, alkylsulfonyl, alkylsulfonyloxy, arylsulfonyl, arylsulfonyloxy, sulfonic acid ester, alkyl ester, aryl ester, urea, phosphoryl, nitro, -U ₃ -V ₅ , V ₆ ,-(C (R _o ) (R _p )) _k1 -U ₃ -V ₅ ,-(C (R _o ) (R _p )) _k1 -U ₃ -V ₃ ,-(C (R _o ) _{(R p)) k1 -U 3} -V 6, - (C (R o) (R p)) is a _{k1 -U 3 -C (O) -V} 6, or binding To the R _e and R _f taken together with the carbon and carbonyl, Methanthial, heterocycle, cycloalkyl group, aryl group, oxime, imine, hydrazone, a bridged cycloalkyl group,

Forming;
R _O and R _P are each independently hydrogen, alkyl, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, arylheterocycle, alkylaryl, alkylcycloalkyl, alkylheterocycle, cycloalkylalkyl, cycloalkylthio, aryl Alkylthio, arylalkylthioalkyl, alkylthioalkyl, cycloalkenyl, heterocyclic alkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, sulfonic acid, sulfonate ester, alkyl Sulfonic acid, arylsulfonic acid, arylalkoxy, alkylthio, arylthio, cyano, aminoalkyl, aminoaryl, ali , Arylalkyl, alkylaryl, carboxamide, alkylcarboxamide, arylcarboxamide, amidyl, carboxyl, carbamoyl, alkylcarboxylic acid, arylcarboxylic acid, alkylcarbonyl, arylcarbonyl, ester, carboxylic acid ester, alkylcarboxylic acid ester, arylcarboxylic acid Ester, sulfonamide, alkylsulfonamide, arylsulfonamide, alkylsulfonyl, alkylsulfonyloxy, arylsulfonyl, arylsulfonyloxy, sulfonic acid ester, alkyl ester, aryl ester, urea, phosphoryl, nitro, -U ₃ -V ₅ , a V _6, or a bond to R _O and R _P taken together with the carbon and carbonyl, Methanthial, heterocycle, cycloalkyl group, Aryl group, oxime, imine, hydrazone, a bridged cycloalkyl group,

Forming;
Z ₅ is -CH ₂ or oxygen;
Z ₆ is -CH or nitrogen;
U ₃ is oxygen, sulfur or -N (R _a ) R _i ;
V ₅ is -NO or -NO ₂ (i.e., nitric oxide);
k _l is an integer from 1 to 3;
R _a is a lone pair, hydrogen or an alkyl group;
_Ri is hydrogen, alkyl, aryl, alkylcarboxylic acid, arylcarboxylic acid, alkylcarboxylic acid ester, arylcarboxylic acid ester, alkylcarboxamide, arylcarboxamide, alkylaryl, alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy, arylsulfinyl, aryl sulfonyl, arylsulfonyloxy, sulfonamido, carboxamido, carboxylic acid esters, aminoalkyl, _{aminoaryl, -CH 2 -C- (U 3 -V} 5) (R e) (R f), there a bond with an adjacent atom A bond that provides a double bond to the atom or M ₁ ⁺ is an organic or inorganic cation-(N ₂ O _2- ) · M ₁ ⁺ ; and
V ₃ and V ₆ are as defined herein.

When R _e and R _f are independently a heterocycle, or R _e and R _{f taken} together are a heterocycle, then R _i is an optional disubstituted nitrogen substituent contained within the radical may also be, R _i is as defined herein.

Nitrosothiols can be prepared by various synthetic methods. In general, the thiol precursor is first prepared and then converted to the S-nitrosothiol derivative by nitrosation of the thiol group with NaNO ₂ under acidic conditions (pH is about 2.5) resulting in the S-nitroso derivative. Acids that can be used for this purpose include aqueous sulfuric acid, aqueous acetic acid and aqueous hydrochloric acid. Thiol precursors can also be nitrosated by reaction with organic nitrites such as tert-butyl nitrite or nitrosonium salts such as tetrafluoroborate nitrosonium in an inert solvent.

  Another group of NO adducts used in the present invention, in which the NO adduct is a compound that donates, transfers or releases nitric oxide, contains at least one ON-O- or ON-N- group There are compounds. A compound containing at least one ON-O- or ON-N- group is preferably an ON-O- or ON-N-polypeptide (the term "polypeptide" possesses a confirmed biological function ON-O- or ON-N-amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); ON-O- or ON-N -Sugars; modified or unmodified ON-O- or ON-N-oligonucleotides (comprising at least 5 nucleotides, preferably 5 to 200 nucleotides); linear or branched, saturated or unmodified Saturated, aliphatic or aromatic, substituted or unsubstituted ON-O- or ON-N-hydrocarbons; and ON-O-, ON-N- or ON-C-heterocyclic compounds. Examples of compounds containing at least one ON-O- or ON-N- group include butyl nitrite, isobutyl nitrite, tert-butyl nitrite, amyl nitrite, isoamyl nitrite, N-nitrosamine, N-nitroso Amides, N-nitrosoureas, N-nitrosoguanidines, N-nitrosocarbamates, N-acyl-N-nitroso compounds (e.g., N-methyl-N-nitrosourea); N-hydroxy-N-nitrosamines, cuprons, alanosine, Dopastin, 1,3-disubstituted nitrosiminobenzimidazole, 1,3,4-thiadiazole-2-nitrosimine, benzothiazole-2 (3H) -nitrosimine, thiazole-2-nitrosimine, oligonitrososide nonimine, 3- Examples include alkyl-N-nitroso-sidnonimine and 2H-1,3,4-thiadiazine nitrosimine.

Among the other groups of NO adducts used in the present invention are those that donate, transfer or release nitric oxide, such as compounds containing at least one O ₂ NO-, O ₂ NN- or O ₂ NS-group. There is a nitrate to do. Among these compounds are O ₂ NO-, O ₂ NN- or O ₂ NS-polypeptides (the term “polypeptide” refers to proteins that do not possess a confirmed biological function, as well as polyamino acids, O ₂ NO-, O ₂ NN- or O ₂ NS-amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); O ₂ NO-, O ₂ NN- Or O ₂ NS-sugar; modified or unmodified O ₂ NO-, O ₂ NN- or O ₂ NS-oligonucleotide (comprising at least 5 nucleotides, preferably 5 to 200 nucleotides); linear Or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O ₂ NO-, O ₂ NN- or O ₂ NS-hydrocarbons; and O ₂ NO-, O ₂ NN- or O _{There are 2} NS-heterocyclic compounds. Examples of compounds containing at least one O ₂ NO-, O ₂ NN- or O ₂ NS- group include isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityl tetranitrate, mannitol hexanitrate, nitroglycerin, pentapentanitrate. Erythritol, pentrinitrol, propatyl nitrate and, for example, SPM 3672, SPM 4757, SPM 5185, SPM 5186 and the disclosures of each are incorporated herein by reference in their entirety, U.S. Patent Nos. 5,284,872, No. 5,661,129, No. 5,807,847 and No. 5,883,122, and those disclosed in International Publication No. 97/46521, International Publication No. 00/54756, and International Publication No. 03/013432. Examples thereof include organic nitrates having a sulfhydryl-containing amino acid.

Another group of NO adducts are N-oxo-N-nitrosamines that donate, transfer or release nitric oxide and have the formula R ^{1 ''} R ^{2 ''} NN (OM ⁺ ) -NO, where R ^{1 ''} and R ^{2 ''} are each independently a polypeptide, amino acid, sugar, modified or unmodified oligonucleotide, linear or branched, saturated or unsaturated, aliphatic or aromatic, substituted or non- A substituted hydrocarbon, or heterocyclic group, represented by the above formula wherein M ₁ ⁺ is an organic or inorganic cation such as, for example, an alkyl-substituted ammonium cation or a Group I metal cation.

  The invention also stimulates endogenous NO or increases endogenous endothelium-derived relaxing factor (EDRF) levels in vivo or is oxidized to produce nitric oxide and / or to nitric oxide synthase and / or cytochrome P450 A compound that is a substrate is targeted. Such compounds include, for example, nitrosated and / or nitrosylated analogs (e.g., nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy) that can be oxidized in vivo to produce nitric oxide. L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosated and nitrosylated L-homoarginine), including L-arginine, L-homoarginine, and N-hydroxy-L-arginine, N-hydroxy- Examples thereof include L-homoarginine, N-hydroxydebrisoquin, N-hydroxypentamidine, N-hydroxyguanidine compound, amidoxime, ketoxime and aldoxime compound. Examples of compounds that can serve as a substrate for cytochrome P450 include, for example, imino (benzylamino) methylhydroxylamine, imino (((4-methylphenyl) methyl) amino) methylhydroxylamine, imino (((4-methoxyphenyl) methyl) Amino) methylhydroxylamine, imino ((((4- (trifluoromethyl) phenyl) methyl) amino) methylhydroxylamine, imino ((((4-nitrophenyl) methyl) amino) methylhydroxylamine, (butylamino) iminomethyl Hydroxylamine, imino (propylamino) methylhydroxylamine, imino (pentylamino) methylhydroxylamine, imino (propylamino) methylhydroxylamine, imino ((methylethyl) amino) methylhydroxylamine, (cyclopropylamino) iminomethylhydroxyl Amine Imino-2-1,2,3,4-tetrahydroisoquinolylmethylhydroxylamine, imino (1-methyl (2-1,2,3,4-tetrahydroisoquinolyl)) methylhydroxylamine, (1,3 -Dimethyl (2-1,2,3,4-tetrahydroisoquinolyl)) iminomethylhydroxylamine, (((4-chlorophenyl) methyl) amino) iminomethylhydroxylamine, ((4-chlorophenyl) amino) iminomethyl Precursors of L-arginine including hydroxylamine, (4-chlorophenyl) (hydroxyimino) methylamine, and 1- (4-chlorophenyl) -1- (hydroxyimino) ethane, such as citrulline, ornithine, glutamine, lysine Substances and / or physiologically acceptable salts thereof, polypeptides comprising at least one of these amino acids, inhibitors of the enzyme arginase (e.g. N-hydroxy-L-arginine and And 2 (S) -amino-6-boronohexanoic acid), e.g., pyruvate, pyruvate precursor, α-keto acid having 4 or more carbon atoms, α-keto having 4 or more carbon atoms Nitric oxide mediators and / or physiologically acceptable salts thereof, including acid precursors (as disclosed in WO 03/017996, hereby incorporated in its entirety by disclosure), and Substrates for nitric oxide synthase, cytokines, adenosine, bradykinin, calreticulin, bisacodyl and phenolphthalein. EDRF is a vasorelaxant secreted by the endothelium and has been identified as nitric oxide (NO) or its closely related derivative (Palmer et al, Nature, 327: 524-526 (1987); Ignarro et al, Proc. Natl. Acad. Sci. USA, 84: 9265-9269 (1987)).

  The present invention is also directed to nitric oxide enhancing compounds that can increase endogenous nitric oxide. Examples of such compounds include substituted 2,2,6,6-tetramethyl-1-piperidinyloxy compounds, substituted 2,2,5,5-tetramethyl-3-pyrrolin-1-oxyl compounds, Substituted 2,2,5,5-tetramethyl-1-pyrrolidinyloxyl compound, substituted 1,1,3,3-tetramethylisoindoline-2-yloxyl compound, substituted 2,2,4,4-tetramethyl -1-oxazolidinyl-3-oxyl compound, substituted 3-imidazolin-1-yloxy, 2,2,5,5-tetramethyl-3-imidazolin-1-yloxyl compound, OT-551, 4-hydroxy-2,2 , 6,6-tetramethyl-1-piperidinyloxy (tempol) and the like, including but not limited to nitroxide-containing compounds. Suitable substituents are aminomethyl, benzoyl, 2-bromoacetamide, 2- (2- (2-bromoacetamido) ethoxy) ethylcarbamoyl, carbamoyl, carboxy, cyano, 5- (dimethylamino) -1-naphthalenesulfonamide, Ethoxyfluorophosphinyloxy, ethyl, 5-fluoro-2,4-dinitroanilino, hydroxy, 2-iodoacetamide, isothiocyanato, isothiocyanatomethyl, methyl, maleimide, maleimidoethyl, 2- (2-maleimidoethoxy) ethylcarbamoyl , Maleimidomethyl, maleimide, oxo, phosphonooxy, and the like.

The present invention also relates to the compounds and compositions of the present invention in part or in full, for example, aldosterone antagonists, α-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin converting enzyme (ACE) inhibitors, antidiabetics Compounds, antihyperlipidemic compounds, antioxidants, antithrombotic and vasodilatory compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H ₂ receptor antagonists , Neutral endopeptidase inhibitors, non-steroidal anti-inflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, thrombocytopenia, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) Inhibitors, and these It is based on the discovery that it can be used in combination with other therapeutic agents for combination therapy instead of other therapeutic agents, such as a combination of two or more of the above. The therapeutic agent may optionally be nitrosated and / or nitrosylated and / or contain at least one heterocyclic nitric oxide donor group and / or at least one nitroxide group.

  Suitable aldosterone antagonists include canrenone, potassium canrenoate, drospirenone, spironolactone, eplerenone (INSPRA®), epoxymexrenone, fadrozole, pregn-4-ene-7,21-dicarboxylic acid, 9, 11-epoxy-17-hydroxy-3-oxo, γ-lactone, methyl ester, (7α, 11α, 17β.)-; Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17- Hydroxy-3-oxo-dimethyl ester, (7α, 11α, 17β.)-; 3'H-cyclopropa (6,7) pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6, 7-Dihydro-17-hydroxy-3-oxo-, γ-lactone, (6β, 7β, 11α, 17β)-; Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy -3-oxo-, 7- (1-methylethyl) ester, monopotassium salt, (7α, 11α, 17β.)-; Pregn-4-ene-7,21-dicarboxylic Acid, 9,11-epoxy-17-hydroxy-3-oxo-, 7-methyl ester, monopotassium salt, (7α, 11α, 17β.)-; 3'H-cyclopropa (6,7) pregna-1, 4, 6-triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, γ-lactone, (6β, 7β, 11α)-; 3'H-cyclopropa (6,7) Pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, methyl ester, (6β, 7β, 11α, 17β )-; 3'H-cyclopropa (6,7) pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, monopotassium salt (6β, 7β, 11α, 17β)-; 3'H-cyclopropa (6,7) pregna-1,4,6-triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17 -Hydroxy-3-oxo-, γ-lactone, (6β, 7β, 11α, 17β)-; Pregn-4-ene-7,21-dicarboxylic acid, 9, 11-epoxy-17-hydroxy-3-oxo- , Γ-lac , Ethyl ester, (7α, 11α, 17β)-; pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, 1-methylethyl Ester, (7α, 11α, 17β)-; RU-28318 and the like, but are not limited thereto. Suitable aldosterone antagonists can be found in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995; and in the Merck Index of CD-ROM, 13th edition; and STN Express, file phar and file registry It is described in more detail in the literature, such as above.

  In some embodiments, the aldosterone antagonist is eplerenone or spironolactone (a potassium-sparing diuretic that acts like an aldosterone antagonist). In a more specific embodiment, eplerenone is administered as a single dose per day or as multiple doses in an amount from about 25 milligrams to about 300 milligrams; spironolactone is as a single dose per day or as multiple doses from about 25 milligrams Administer in an amount of about 150 milligrams.

  Suitable α-adrenergic receptor antagonists include phentolamine, tolazoline, idazoxan, deligridol, RX 821002, BRL 44408, BRL 44409, BAM 1303, labetalol, ifenprodil, lauwalsin, corinacin, lauvacin, tetrahydroalstonine, apoyohimbine, Aquamidine, β-yohimbine, yohimbole, yohimbine, pseudoyohimbine, epi-3α-yohimbine, 10-hydroxy-yohimbine, 11-hydroxy-yohimbine, tamsulosin, benoxthian, atipamezole, BE 2254, WB 4101, HU-723, tedisamil, Mirtazipine, cetiptiline, levoxitine, derecamine, naphthopyl, saterinone, SL 89.0591, ARC 239, urapidil, 5-methylurapidil, monatepi, haloperidol, indolamin, SB 216469, mochi Cisirito, trazodone, dapiprozole, efaloxane, recoldachi 15/2739, SNAP 1069, SNAP 5089, SNAP 5272, RS 17053, SL 89.0591, KMD 3213, spiperone, AH 11110A, chloroethyl clonidine, BMY 7378, nigurdipine, etc. It is not limited to these. Suitable α-adrenergic receptor antagonists are described in the literature, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, and CD-ROM, 13th edition and STN Express, It is described in detail in the Merck Index of file phar and file registry.

が挙げられるが、これらに限定されることはない。適当なアンギオテンシンIIアンタゴニストは文献において、例えば、Goodman and Gilman, The Pharmacological Basis of Therapeutics (第9版), McGraw-Hill, 1995、ならびにCD-ROM, 第13版のおよびSTN Express, file phar and file registryのMerck Indexにおいて詳細に記載されている。 Suitable angiotensin II antagonists include angiotensin, abitesartan, candesartan, candesartan cilexetil, erysartan, embusartan, enoltasosartan, eprosartan, von sultan, folasartan, glycyllosartan, irbesartan, losartan, olmesartan, milfasartan , Medoxomil, Lipisartan, Pomisartan, Pratosartan, Saprisartan, Sararasin, Salmesin, Tasosartan, Telmisartan, Valsartan, Zolasartan, 3- (2 '(tetrazol-5-yl) -1,1'-biphen-4-yl) methyl -5,7-dimethyl-2-ethyl-3H-imidazo (4,5-b) pyridine, an antibody against angiotensin II,

However, it is not limited to these. Suitable angiotensin II antagonists are described in the literature, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, and CD-ROM, 13th edition and STN Express, file phar and file registry. In the Merck Index.

  In some embodiments, the angiotensin II antagonist is candesartan, eprosartan, irbesartan, losartan, omlesartan, telmisartan or valsartan. In a more specific embodiment, candesartan is administered as candesartan cilexetil in an amount of about 15 milligrams to about 100 milligrams as a single dose per day or as multiple doses; eprosartan as a single dose or multiple times per day Administered as eprosartan mesylate in a dose of about 400 milligrams to about 1600 milligrams; Irbesartan administered as a single dose per day or as multiple doses from about 75 milligrams to about 1200 milligrams; Losartan per day Administered as losartan potassium in a dose of about 25 milligrams to about 100 milligrams as a single dose or as multiple doses; omlesartan in an amount of about 5 milligrams to about 40 milligrams as a single dose or as multiple doses per day In Olmesartan Medoxomil Telmisartan is administered as a single dose per day or as multiple doses in an amount from about 20 milligrams to about 80 milligrams; valsartan is administered as a single dose per day or as multiple doses from about 80 milligrams to about 320 Administer in milligram quantities.

  Suitable angiotensin converting enzyme inhibitors (ACE inhibitors) include alacepril, benazepril (LOTENSIN (registered trademark), CIBACEN (registered trademark)), benazeprilat, captopril, celonapril, cilazapril, delapril, duinapril, enalapril, enalapril, cido Hoshinopril, Hoshinoprilat, Gemopatrilato, Glycopril, Idrapril, Imidapril, Lisinopril, Moexipril, Mobiletipril, Naftopidil, Omapatrirat, Pentopril, Perindopril, Perindoprilato, Quinapril, Quinaprilate, Ramiprilate, Ramipril , Trandolaprilat, urapidil, zofenopril, acyl mercapto and merca Ptoalkanoylproline (mercaptoalkanoyl pralines), carboxyalkyl dipeptide, carboxyalkyl dipeptide, phosphinylalkanoyl pralines, registration number 796406, AVE 7688, BP1.137, CHF 1514, E 4030, ER 3295, FPL-66564, Examples include, but are not limited to, MDL 100240, RL 6134, RL 6207, RL 6893, SA 760, S-5590, and Z 13752A. Suitable angiotensin converting enzyme inhibitors are described in the literature, for example in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, and CD-ROM, 12th edition, version 12: 1, 1996. And in the Merck Index of STN Express, file phar and file registry.

  In some embodiments, the angiotensin converting enzyme inhibitor is benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril, trandolapril or trandolapril. In a more specific embodiment, benazepril is administered as benazepril hydrochloride as a single dose per day or as multiple doses in an amount of about 5 milligrams to about 80 milligrams; captopril is administered as a single dose or as multiple doses per day. Administered in an amount of 12.5 milligrams to about 450 milligrams; Enalapril administered as a single dose per day or as multiple doses as enalapril maleate in an amount of about 2.5 milligrams to about 40 milligrams; Hosinopril as a single dose per day Or administered as fosinopril sodium in an amount of about 5 milligrams to about 60 milligrams as multiple doses; lisinopril administered as a single dose or as multiple doses in an amount of about 2.5 milligrams to about 75 milligrams per day; moexipril As a single dose or multiple times per day Administered as moexipril hydrochloride in an amount of about 7.5 milligrams to about 45 milligrams; quinapril administered as a single or multiple doses of about 5 milligrams to about 40 milligrams of quinapril hydrochloride; single ramipril per day Administered as ramipril hydrochloride in an amount of about 1.25 milligrams to about 40 milligrams as single or multiple doses; trandolapril administered in an amount of about 0.5 milligrams to about 4 milligrams as single or multiple doses per day; Prilat is administered as a single or multiple doses per day in an amount of about 0.5 milligrams to about 4 milligrams.

  Suitable anti-diabetic compounds include acarbose, acetohexamide, buformin, carbbutamide, chlorpropamide, glibornuride, gliclazide, glimepiride, glipizide, glyxone, glyoxepide, glyburide, glybuthiazole, glybazole, glyhexamide, grimidine, glipinamide, insulin, Examples include, but are not limited to, metformin, miglitol, nateglinide, fenbutamide, phenformin, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, tolcyclamide, troglitazone, voglibose. Suitable antidiabetic compounds are described in the literature, e.g. Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, and CD-ROM, 13th edition and STN Express, file phar and file registry. In the Merck Index.

  Suitable antihyperlipidemic compounds include, for example, atorvastatin (LIPITOR®), velvastatin, cerivastatin (BAYCOL®), dalvastatin, fluindostatin (Sandoz XU-62-320), fluvastatin , Gremvastatin, lovastatin (MEVACOR®), mevastatin, pravastatin (PRAVACHOL®), rosuvastatin (CRESTRO®), simvastatin (ZOCOR®), verostatin (also known as simbinorin) ), Statin or HMG-CoA reductase inhibitors such as VYTORIN® (ezetimibe / simvastatin), GR-95030, SQ 33,600, BMY 22089, BMY 22,566, CI 980; gemfibrozil, cholestyramine, colestipol, Niacin, niacin acid, bile acid inhibitors such as cholestyramine, colesevelam, colestipol, poly (meth -(3-trimethylaminopropyl) imino-trimethylene dihalide) and the like; probucol; e.g. bezafibrate (BezalipTM), beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, etofibrate, fenofibrate (Lipidil (Trademark), Lipidil Micro (trademark), gemfibrozil (Lopid (trademark)), nicofibrate, pilifibrate, lonifibrate, simfibrate, theofibrate, etc. CGS 25159, CP-529414 (torcetrapide), JTT-705, substituted N- [3- (1,1,2,2-tetrafluoroethoxy) benzyl] -N- (3-phenoxyphenyl) -trifluoro-3- Amino-2-propanol, N, N-disubstituted trifluoro-3-amino-2-propanol, PD 140195 (4-phenyl-5- Cholesterol ester transfer protein (CETP) inhibitors such as, but not limited to, Ridecyl-4H-1,2,4-triazole-3-thiol), SC-794, SC-795, SCH 58149, etc. There is nothing.

  In some embodiments, the antihyperlipidemic compound is atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin or simvastatin. In a more specific embodiment, atorvastatin is administered as a single dose per day or as multiple doses in an amount of about 10 milligrams to about 80 milligrams; fluvastatin is administered as a single dose per day or as multiple doses of about 20 milligrams From about 10 milligrams to about 80 milligrams as a single dose per day or as multiple doses; pravastatin as a single dose per day or as multiple doses Administered in an amount of 10 milligrams to about 80 milligrams; rosuvastatin administered as a single dose per day or as multiple doses in an amount of about 5 milligrams to about 40 milligrams; simvastatin as a single dose per day or multiple doses As a dose of about 5 milligrams to about 80 milligrams.

  Suitable antioxidants include, but are not limited to, small molecule antioxidants and antioxidant enzymes. Suitable small molecule antioxidants include hydralazine compounds, glutathione, vitamin C, vitamin E, cysteine, N-acetyl-cysteine, β-carotene, ubiquinone, ubiquinol-10, tocopherol, coenzyme Q, superoxide dismutase mimics, For example, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), DOXYL, PROXYL nitroxide compounds; 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy (Tempol), M-40401, M-40403, M-40407, M-40419, M-40484, M-40587, M-40588 and the like, but are not limited thereto. Suitable antioxidant enzymes include superoxide dismutase, catalase, glutathione peroxidase, NADPH oxidase inhibitor such as apocynin, aminoguanidine, ONO1714, S17834 (benzo (b) pyran-4-one derivative), etc .; xanthine oxidase inhibitor For example, allopurinol, oxypurinol, amflutisol, diethyldithiocarbamate, 2-styrylchromones, chrysin, luteolin, kaempferol, quercetin, myricetin, isorhamnetin, 2,2 ', 4,4'-tetra Benzophenones such as hydroxybenzophenone, 3,4,5,2 ', 3', 4'-hexahydroxybenzophenone and 4,4'-dihydroxybenzophenone; 2-amino-4H-1,3-benzothiazin-4-one, Bennes such as 2-guanidino-4H-1,3-benzothiazin-4-one and rhodanine Thiazinone analogs; N-hydroxyguanidine derivatives such as PR5 (1- (3,4-dimethoxy-2-chlorobenzylideneamino) -3-hydroxyguanidine); 6-formylpterin and the like. There is nothing. The antioxidant enzyme can be delivered by gene therapy as a viral vector and / or a non-viral vector. Suitable antioxidants are described in the literature, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, and CD-ROM, 13th edition and STN Express, file phar and file registry. In the Merck Index.

  In some embodiments, the antioxidant is an apocynin, a hydralazine compound, and a superoxide dismutase mimic.

  Suitable antithrombotic and vasodilatory compounds include abiximab, acetorphan, acetylsalicylic acid, argatroban, bamethane, benflozil, benziodarone, betahistine, bisamil, brobincamine, bufeniod, citicoline, clobenflor, clopidogrel, cyclandelate, dalteparin , Dipyridamole, dropreniramine, enoxaparin, fendiline, ifenprodil, iloprost, indobufen, isvogrel, isoxsuprin, heparin, lamifanban, midrozine, nadroparin, nicotinoyl alcohol, nylidrine, ozagrel, perhexiline, phenylpropanolamine, paveriramine, paverine rein Salt, ridogrel, sloctide, chinofedori , Tinzaparin, triflusal, Bintoperoru, but like hexane Chi Nord Nai reeds sulfonate is not limited thereto. Suitable antithrombotic and vasodilatory compounds are described in the literature, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, and CD-ROM, 13th edition and STN Express, It is described in detail in the Merck Index of file phar and file registry.

  Suitable calcium channel blockers include amlodipine (NORVASC®), anipamil, alanidipine, amrinone, azelnidipine, balnidipine, benciclin, benidipine, bepridil, cilnidipine, cinnarizine, clentiazem, diltiazem, dotaridine, efonidipine, ergonodipine, Fallon, felodipine, fendiline, flunarizine, flupirylene, flunidipine, galopamil, ipenoxazone, isradipine, rasidipine, remildipine, lercanidipine, lomerizine, manidipine, mibefradil, monatepyr, nicardipine, nifedipine, nigurdipine, nididipine, nididipine, nildipine Oxodipine, perhexiline, phenytoin Phenytprenylamine, pranidpine, ranolazine, lyosidine, cemothiazyl, tamorridine, temiverine hydrochloride, terodiline, thiapamil, batanidipine hydrochloride, verapamil, ziconotide, AE-0047, CAI, JTV-519, CHF-1521, L-651582, NS-7, NW-1015, RO-2933, SB-237376, SL-34.0829-08, S-312d, SD-3212, TA-993, YM-430, etc. Absent. Suitable calcium channel blockers are described in the literature, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, and CD-ROM, 13th edition and STN Express, file phar and file It is described in detail in the Merck Index of the registry.

  In some embodiments, the calcium channel blocker is amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, verapamil.

  Suitable digitalis include, but are not limited to, digoxin and digoxitin. In some embodiments, digoxin is administered to achieve a steady state serum concentration of at least about 0.7 nanogram / ml to about 2.0 nanogram / ml.

  Suitable diuretics include thiazides (e.g., althiazide, bendroflumethiazide, benzchlortriazide, benzhydrochlorothiazide, benzthiazide, butiazide, chlorothiazide, cyclopenthiazide, cyclothiazide, epithiazide, ethiazide, hydrobenze. (Such as thiazide, hydrochlorothiazide, hydroflumethiazide, methylcrothiazide, methylcyclothiazide, penflutazide, polythiazide, tecrotiazide, trichlormethiazide, triflumetazide, etc.); , Butazolamide, butizide, canrenone, carperitide, chloraminophenamide, chlorazanil, chlormelodrine, chlorthalide , Cicletanide, clofenamide, clopamide, chlorexolone, conivaptan, daglutril, dichlorophenamide, disulfamide, ethacrynic acid, ethoxazolamide, etzoline, phenoldopam, fenxone, furosemide, indapamide, mebutizide, mebutizide Mercaptomerin sodium, mercumallylic acid, mersaryl, metazolamide, methiclan, metolazone, mozabaptan, muzolimine, N- (5-1,3,4-thiadiazol-2-yl) acetamide, nesiritide, pamabrom, paraflutide, piretanide, Protheobromine, kinetazone, scoparius, spironolactone, theobromine, ticrinafen, torsemide, tolvaptan, triamterene, Trypamide, uralitide, xypamide or potassium, AT 189000, AY 31906, BG 9928, BG 9791, C 2921, DTI 0017, JDL 961, KW 3902, MCC 134, SLV 306, SR 121463, WAY 140288, ZP 120, etc. However, it is not limited to these. Suitable diuretics are described in the literature, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, and CD-ROM, 13th edition and STN Express, file phar and file registry. It is described in detail in the Merck Index.

  Depending on the diuretic used, potassium can also be administered to the patient to optimize fluid balance while avoiding hypokalemic alkalosis. Administration of potassium may be in the form of potassium chloride or by daily intake of foods with high potassium content such as, for example, banana or orange juice. Methods of administration of these compounds are described in further detail in US Pat. No. 4,868,179, the disclosure of which is hereby incorporated by reference in its entirety.

  In some embodiments, the diuretic is amiloride, furosemide, chlorthalidone, hydrochlorothiazide, or triamterene. In a more specific embodiment, amiloride is administered as amiloride hydrochloride in an amount of about 5 milligrams to about 15 milligrams as a single dose or as multiple doses per day; furosemide as a single dose or as multiple doses per day Administered in an amount of 10 milligrams to about 600 milligrams; Chlortalidone administered as a single dose per day or as multiple doses in an amount of about 15 milligrams to about 150 milligrams; Hydrochlorothiazide as a single dose per day or as multiple doses Is administered in an amount of about 12.5 milligrams to about 300 milligrams; triamterene is administered in an amount of about 35 milligrams to about 225 milligrams as a single dose or as multiple doses per day.

  Suitable endothelin antagonists include, but are not limited to, atrasentan, bosentan, darsentan, endothelin, enlasentan, sitaxsentan, sulfonamide endothelin antagonist, tezosentan, BMS 193884, BQ-123, SQ 28608, etc. . Suitable endothelin antagonists are described in the literature, e.g. Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, and CD-ROM, 13th edition and STN Express, file phar and file registry. It is described in detail in the Merck Index.

式中でa、bおよびcは独立して単結合または二重結合であり; R₁およびR₂はそれぞれ独立して水素、アルキル、エステルまたは複素環であって、アルキル、エステルおよび複素環は本明細書において規定されるとおりであり; R₃およびR₄はそれぞれ独立して孤立電子対または水素であり、但しR₁、R₂、R₃およびR₄の少なくとも1つは水素ではない。例示的なヒドララジン化合物としては、ブドララジン、カドララジン、ジヒドララジン、エンドララジン、ヒドララジン、ピルドララジン、トドララジンなどが挙げられる。適当なヒドララジン化合物は文献において、例えば、Goodman and Gilman, The Pharmacological Basis of Therapeutics (第9版), McGraw-Hill, 1995、ならびにCD-ROM, 第13版のおよびSTN Express, file phar and file registryのMerck Indexにおいて詳細に記載されている。 Suitable hydralazine compounds include, but are not limited to, compounds having the following formula:

Where a, b and c are independently a single bond or a double bond; R ₁ and R ₂ are each independently hydrogen, alkyl, ester or heterocycle, wherein alkyl, ester and heterocycle are As defined herein; R ₃ and R ₄ are each independently a lone pair or hydrogen, provided that at least one of R ₁ , R ₂ , R ₃ and R ₄ is not hydrogen. Exemplary hydralazine compounds include budralazine, cadralazine, dihydralazine, endralazine, hydralazine, pyrudrazine, todralazine and the like. Suitable hydralazine compounds are described in the literature, e.g. Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, and CD-ROM, 13th edition and STN Express, file phar and file registry. It is described in detail in the Merck Index.

  In some embodiments, the hydralazine compound is a pharmaceutically acceptable salt thereof such as hydralazine or hydralazine hydrochloride. In a more specific embodiment, hydralazine is administered as hydralazine hydrochloride in an amount of about 10 milligrams to about 300 milligrams as a single dose or multiple doses per day.

Suitable H ₂ receptor antagonists include, but are not limited to, brimamide, cimetidine, ebrotidine, famotidine, nizatidine, loxatidine, lantidine, thiotidine and the like. Suitable H ₂ receptor antagonists are described in the literature, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, Pgs. 901-915; CD-ROM, 13th edition Merck Index. And in WO 00/28988 issued to NitroMed Inc., the disclosures of which are incorporated herein by reference in their entirety.

  Suitable neutral endopeptidase inhibitors include, but are not limited to, atrial natriuretic peptide, diazapine, azepinone, ecadotolyl, fasidotolyl, faside trilato, omapatrilato, sampatrilato, BMS 189,921, Z 13752 A, etc. Absent. Neutral endopeptidase inhibitors are described in the literature, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, and CD-ROM, 13th edition and STN Express, file phar and file It is described in detail in the Merck Index of the registry.

  Suitable NSAIDs include acetaminophen, acemetacin, aceclofenac, aluminoprofen, ampenac, bendazac, benoxaprofen, bronfenac, bucloxic acid, butybufen, carprofen, synmethacin, clopirac, diclofenac, etodolac, felbinac, fenclozic acid, Fenbufen, fenoprofen, fenthiazak, flunoxaprofen, flurbiprofen, ibufenac, ibuprofen, indomethacin, isofezolak, isoxepac, indoprofen, ketoprofen, lonazolac, loxoprofen, methiazine acid, mofezolac, miloprofen, naproxenol, oxaprozine, (pirozolac), pyrprofen, pranoprofen, protidic acid, salicy Amides, sulindac, suprofen, sukibzon, thiaprofenic acid, tolmetine, xembucin, xymoprofen, zaltoprofen, zomepirac, aspirin, acemethosin, bumadizone, carprofenac, cridanac, diflunisal, enfenamic acid, fendsal, flufenamic acid, fluniken gentis Examples include, but are not limited to, meclofenamic acid, mefenamic acid, mesalamine, and prodrugs thereof. Suitable NSAIDs are found in the literature, for example in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, Pgs. 617-657; CD-ROM, 13th edition Merck Index; and NitroMed US Pat. Nos. 6,057,347 and 6,297,260 issued to Inc., the disclosures of which are hereby incorporated by reference in their entirety.

  In some embodiments, the NSAIDs are acetaminophen, diclofenac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen or aspirin. In a more specific embodiment, acetaminophen is administered as a single dose per day or as multiple doses in an amount of about 325 milligrams to about 4 grams; diclofenac is administered as a single dose or as multiple doses per day. Administered in an amount from milligrams to about 250 milligrams; flurbiprofen is administered as a single dose per day or as multiple doses in an amount of about 100 milligrams to about 300 milligrams; ibuprofen is administered as a single dose per day or multiple Administered in a dose of about 400 milligrams to about 3.2 grams; indomethacin administered as a single daily dose or in multiple doses from about 25 milligrams to about 200 milligrams; ketoprofen as a single daily dose Or in multiple doses in an amount of about 50 milligrams to about 300 milligrams; naproxen In a dose of about 250 milligrams to about 1.5 grams as a single dose or as multiple doses per day; aspirin in a dose of about 10 milligrams to about 2 grams as a single dose or multiple doses per day .

  Suitable phosphodiesterase inhibitors include filaminast, picramirast, rolipram, Org 20241, MCI-154, roflumilast, tobolinone, political, lyxazinone, zaprinast, sildenafil, pyrazolopyrimidinone, motapizone, pimobendan, sardaverine, ciguazodan, 930 EMD 53998, imazodan, saterinone, roprinone hydrochloride, 3-pyridinecarbonitrile derivative, acephylline, albifylline, bamiphylline, denbuphyllene, diphylline, doxophilin, etophylline, tolvaphyrin, theophylline, nanterinone, pentoxophilin, proxyphylline, cilostazol, cilostazol, MS 857, Piroximon, Milrinone, Amrinone, Trafenthrin, Dipyridamole, Papaveroline, E4021, Thienopyri Gin derivative, Triflusal, ICOS-351, Tetrahydropiperazino (1,2-b) β-carboline-1,4-dione derivative, Carboline derivative, 2-pyrazolin-5-one derivative, Fusion pyridazine derivative, Quinazoline derivative, Anthranilic acid derivatives, imidazoquinazoline derivatives, tadalafil, vardenafil, and Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, Inc. (1995), The Physician's Desk Reference (49th edition), Medical Economics (1995), Drug Facts and Comparisons (1993 edition), Facts and Comparisons (1993), and CD-ROM, those in the 13th edition Merck Index, but are not limited to these. Phosphodiesterase inhibitors and nitrosated and / or nitrosylated derivatives thereof have been reissued as U.S. Patent Nos. 5,932,538, 5,994,294, 5,874,437, U.S. Reissue Patent No. 0377234, U.S. Pat. No. 6,172,060, No. 6,197,778, No. 6,177,428, No. 6,172,068, No. 6,221,881, No. 6,232,321, No. 6,197,782, No. 6,133,272, No. 6,211,179, No. 6,316,457 and No. No. 6,331,542, the disclosure of each of these patents is hereby incorporated by reference in its entirety.

  Suitable potassium channel blockers include nicorandil, pinacidil, cromakalim (BRL 34915), apricarim, bimacarim, emacarim, remacalim, minoxidil, diazoxide, 9-chloro-7- (2-chlorophenyl) -5H-pyrimido (5,4 , -d) (2) -Benzazepine, Ribi, CPG-11952, CGS-9896, ZD 6169, Diazoxide, Bay X 9227, P1075, Bay X 9228, SDZ PCO 400, WAY-120,491, WAY-120,129, Ro 31- 6930, SR 44869, BRL 38226, S 0121, SR 46142A, CGP 42500, SR 44994, fumaric acid alkylide, lorazepam, temazepam, rilmazaphone, nimetazepam, midazolam, lormetazepam, loprazolam, ibutilide fumarate, haloxazolam, flunitrazepam, flunitrazepam, flunitrazepam Examples include, but are not limited to, clonazepam, sinorazepam, brotizolam, and the like. Suitable potassium channel blockers are described in the literature, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, and CD-ROM, 13th edition and STN Express, file phar and file It is described in detail in the Merck Index of the registry.

  Suitable thrombocytopenic agents include, for example, ancrod, anistreplase, lactobisobrin, brinolase, Hageman factor (i.e., factor XII) fragments such as streptokinase, tissue plasminogen activator (TPA), urokinase, Fibrinolytics such as prourokinase, recombinant TPA, plasmin, plasminogen activator such as plasminogen; factor Xa, factor TFPI, factor VIIa, factor IXc, factor Va, factor VIIIa Anticoagulants including, but not limited to, inhibitors of factors, other clotting factors, etc .; vitamin K antagonists such as coumarin, coumarin derivatives (e.g., warfarin sodium); e.g., unfractionated Glycosaminoglycans such as both heparin and low molecular weight forms; sodium ardeparin, bivalyl , Brominedione, coumarin, dalteparin sodium, danaparoid sodium; dazoxiben hydrochloride, decylzine, dicoumarol, ephegatran sulfate, enoxaparin sodium, ifetroban, ifetroban sodium, riaporate sodium, nafamostat mesylate, fenprocomon, sulfatide, Tinzaparin sodium, reteplase; trifenagrel, warfarin, dextran, etc .; abciximab, acadesine, anipamyl, argatroban, aspirin, clopidogrel, diadenosine 5 ', 5' ''-P1, P4-tetraphosphate (Ap4A) analog, difibrotide, Dilazep dihydrochloride, dipyridamole, dopamine, 3-methoxytyramine, glucagon, for example, glycoprotein IIb / IIIa antagonists such as Ro-43-8857, L-700,462, Iro Lost, isocarbacycline methyl ester, itazigrel, ketanserin, BM-13.177, lamifane, rifalizine, molsidomine, nifedipine, oxagrelate, prostaglandins such as lexipafant, prostacyclin, pyrazine, pyridinol carbamate, ReoPro ( That is, abciximab), sulfinpyrazone, synthetic compounds BN-50727, BN-52021, CV-4151, E-5510, FK-409, GU-7, KB-2796, KBT-3022, KC-404, KF-4939 , OP-41483, TRK-100, TA-3090, TFC-612, ZK-36374, 2,4,5,7-tetrathiaoctane, 2,4,5,7-tetrathiaoctane 2,2-dioxide, Platelet activating factor antagonists such as 2,4,5-trithiahexane, theophyllin, pentoxifyllin, such as picotamide, throtroban, ticlopidine, tirofiban, trapidil, Thromboxane and thromboxane synthase inhibitors such as clopidine, triphenagrel, trilinolein, 3-substituted 5,6-bis (4-methoxyphenyl) -1,2,4-triazine; antibodies against glycoprotein IIb / IIIa; for example Anti-serotonins such as clopridogrel; sulfinpyrazone; aspirin; dipyridamole; clofibrate; pyridinol carbamate; glucagon, caffeine; theophylline, pentoxyphyllin; ticlopidine, etc. It will never be done.

  Suitable proton pump inhibitors include disulfrazole, esomeprazole, lansoprazole, leminoprazole, omeprazole, pantoprazole, rabeprazole, timoprazole, tenatoprazole, 2- (2-benzimidazolyl) -pyridine, tricyclic imidazole, Thienopyridine benzimidazole, fluoroalkoxy-substituted benzimidazole, dialkoxybenzimidazole, N-substituted 2- (pyridylalkenesulfinyl) benzimidazole, cycloheptenepyridine, 5-pyrrolyl-2-pyridylmethylsulfinylbenzimidazole, alkylsulfinylbenzimidazole, Fluoro-pyridylmethylsulfinylbenzimidazole, imidazo (4,5-b) pyrididine, RO 18-5362, IY 81149, 4-amino-3-carbonylquinoline, 4-amino-3-acy Naphthylide, 4-aminoquinoline, 4-amino-3-acylquinoline, 3-butyryl-4- (2-methylphenylamino) -8- (2-hydroxyethoxy) quinoline, quinazoline, tetrahydroisoquinolin-2-ylpyrimidine, YH 1885, 3-substituted 1,2,4-thiadiazolo (4,5-a) benzimidazole, 3-substituted imidazo (1,2-d) -thiadiazole, 2-sulfinylnicotinamide, pyridylsulfinylbenzimidazole, pyridylsulfinyl Thienoimidazole, thienoimidazole-toluidine, 4,5-dihydrooxazole, thienoimidazole-toluidine, Hoe-731, imidazo (1,2-a) pyridine, pyrrolo (2,3-b) pyridine, etc. It is not limited to. Suitable proton pump inhibitors are described in the literature, e.g. Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995; CD-ROM, 13th edition Merck Index; and NitroMed Inc. It is described in detail in the assigned WO 00/50037, the disclosure of which is hereby incorporated by reference in its entirety.

  Suitable renin inhibitors include aliskiren (SPP-100), ditexylene, enalkrein (A-64662), medullipin, terlkiren, tonin, zankilen, RO 42-5892 (remixylene), A 62198, A64662, A65317, A69729, A72517 (Zankilen), A74273, CP80794, CGP 29287, CGP-38560A, EMD47942, ES305, ES1005, ES8891, FK906, FK744, H113, H-142, KRI 1314, Pepstatin A, RO 44-9375 (Cyproxylene), RO 42-5892, RO 66-1132, RO 66-1168, SP 500, SP 800, SR-43845, SQ 34017, U 71038, YM -21095, YM-26365, urea derivatives of peptides, amino acids linked by non-peptide bonds, di- and tri-peptide derivatives (e.g., Act-A, Act-B, Act-C, ACT-D, etc.), amino acids And its derivatives, diolsulfonamides and sulfinyls, modified peptides, peptidyl β-aminoacylaminodiols Formate, although monoclonal antibodies are exemplified for renin, is not limited thereto. Suitable renin inhibitors are disclosed in U.S. Patent Nos. 5,116,835, 5,114,937, 5,106,835, 5,104,869, 5,095,119, each of which is incorporated herein by reference in its entirety. No. 5,098,924, No. 5,095,006, No. 5,089,471, No. 5,075,451, No. 5,066,643, No. 5,063,208, No. 4,845,079, No. 5,055,466, No. 4,980,283, No. 4,885,292 In 4,780,401, 5,071,837, 5,064,965, 5,063,207, 5,036,054, 5,036,053, 5,034,512, and 4,894,437; and in literature, for example, Goodman and It is described in detail in Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995, and the Merck Index of CD-ROM, 13th edition and STN Express, file phar and file registry.

  Suitable COX-2 inhibitors include nimesulide, celecoxib (CELEBREX®), etoroxib (ARCOXIA®), flosslide, lumiracoxib (PREXIG®, COX-189), parecoxib (DYNSTAT®) Trademark)), rofecoxib (VIOXX (registered trademark)), thylakoxib (JTE-522), valdecoxib (BEXTRA (registered trademark)), ABT 963, BMS 347070, CS 502, DuP 697, GW-406381, NS-386, SC -57666, SC-58125, SC-58635, and the like, and mixtures of two or more thereof. Suitable COX-2 inhibitors are disclosed in U.S. Pat.Nos. 5,344,991, 5,380,738, 5,393,790, 5,409,944, 5,434,178, the disclosures of each of which are incorporated herein by reference in their entirety. No. 5,436,265, No. 5,466,823, No. 5,474,995, No. 5,510,368, No. 5,536,752, No. 5,550,142, No. 5,552,422, No. 5,604,253, No. 5,604,260, No. 5,639,780 Nos. 5,932,598 and 6,633,272, and International Publication Nos. 94/03387, 94/15723, 94/20480, 94/26731, 94/27980 No. 95/00501, No. 95/15316, No. 96/03387, No. 96/03388, No. 96/06840, No. 96/21667, No. 96/31509, No. 96/36623, No. 97/14691, No. 97/16435, No. 01/45703 and No. 01/87343; and literature, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th edition), McGraw-Hill, 1995 CD-ROM into the beauty, the 13th edition of the and STN Express, in the Merck Index of file phar and file registry.

  In some embodiments, the COX-2 inhibitor is celecoxib, etlicoxib, luminacoxib, parecoxib, rofecoxib or valdecoxib. In a more specific embodiment, celecoxib is administered as a single dose per day or as multiple doses in an amount of about 100 milligrams to about 800 milligrams; etoroxib is administered as a single dose per day or as multiple doses from about 50 milligrams Administered in an amount of about 200 milligrams; Lumiracoxib administered as a single dose per day or as multiple doses in an amount of about 40 milligrams to about 1200 milligrams; Parecoxib as a single dose per day or as multiple doses of about 20 Administered in an amount from milligrams to about 100 milligrams; Rofecoxib administered as a single dose per day or as multiple doses in an amount from about 12.5 milligrams to about 50 milligrams; Valdecoxib as a single dose per day or as multiple doses Administer in an amount of about 10 milligrams to about 40 milligrams.

  The invention includes in one or more pharmaceutically acceptable carriers (i) a nitric oxide enhanced diuretic compound or a pharmaceutically acceptable salt thereof, and (ii) an aldosterone antagonist, an angiotensin II antagonist, an angiotensin converting enzyme ( ACE) inhibitors, β-adrenergic antagonists, diuretics, and compositions comprising at least one compound selected from the group consisting of hydralazine compounds. In other embodiments of the invention, the aldosterone antagonist is eplerenone or spironolactone; the angiotensin II antagonist is candesartan cilexetil, eprosartan mesylate, irbesartan, losartan potassium, medoxomil, telmisartan, trandolapril, trandolaprilato or valsartan Angiotensin converting enzyme inhibitors are benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril hydrochloride, quinapril hydrochloride, ramipril; β-adrenergic antagonists are bisoprolol fumarate, carvedilol tartrate, metoprolol tartrate, Propranolol hydrochloride or timolol maleate; calcium channel blockers are Mlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, verapamil; diuretic is amiloride hydrochloride, chlorthalidone, hydrochlorothiazide or triamterene; and renin inhibitors are aliskiren, cyproxylene, ditexylene, alkynal Medullipin, remiquiren, terlkiren, tonin or zankiren.

  The present invention comprises (i) a nitric oxide enhancing diuretic compound or a pharmaceutically acceptable salt thereof, and (ii) a nitric oxide enhancing compound such as isosorbide dinitrate and / or isosorbide mononitrate (preferably isosorbide dinitrate); (i) A composition comprising a hydralazine compound (such as hydralazine hydrochloride) is provided. In one embodiment, hydralazine hydrochloride can be administered in an amount from about 30 milligrams per day to about 400 milligrams per day; isosorbide dinitrate can be administered in an amount from about 10 milligrams per day to about 200 milligrams per day. Or isosorbide mononitrate can be administered in an amount of about 5 milligrams per day to about 120 milligrams per day. In another embodiment, hydralazine hydrochloride can be administered in an amount from about 50 milligrams per day to about 300 milligrams per day; isosorbide dinitrate can be administered in an amount from about 20 milligrams per day to about 160 milligrams per day. Or isosorbide mononitrate can be administered in an amount from about 15 milligrams per day to about 100 milligrams per day. In yet another embodiment, hydralazine hydrochloride can be administered in an amount of about 37.5 milligrams to about 75 milligrams 1 to 4 times per day; isosorbide dinitrate in an amount of about 20 milligrams to about 40 milligrams 1 to 4 times per day. Or isosorbide mononitrate can be administered in an amount of about 10 milligrams to about 20 milligrams 1 to 4 times per day. In another embodiment of the method of the present invention, the patient can be administered a composition comprising about 225 mg of hydralazine hydrochloride and about 120 mg of isosorbide dinitrate once a day (ie, once a day). In another embodiment of the methods of the invention, the patient can be administered a composition comprising about 112.5 mg of hydralazine hydrochloride and about 60 mg of isosorbide dinitrate twice a day (ie, twice a day). In another embodiment of the method of the present invention, the patient can be administered a composition comprising about 56.25 mg of hydralazine hydrochloride and about 30 mg of isosorbide dinitrate twice a day (ie, twice a day). In another embodiment of the methods of the invention, the patient can be administered a composition comprising about 75 mg hydralazine hydrochloride and about 40 mg isosorbide dinitrate three times a day (ie, three times a day). In another embodiment of the method of the present invention, the patient can be administered a composition comprising about 37.5 mg hydralazine hydrochloride and about 20 mg isosorbide dinitrate three times a day (ie, three times a day). Administer a specific amount of hydralazine and isosorbide dinitrate or isosorbide mononitrate once a day as a single dose; or several times throughout the day in multiple doses; or as a sustained release oral formulation; or as an injectable formulation be able to.

The present invention provides a method of treating conditions resulting from overhydration and / or electrolyte retention by administering an effective amount of a compound and / or composition described herein to a patient in need thereof. For example, the patient can be administered an effective amount of at least one nitric oxide-enhancing diuretic compound. In another embodiment, the patient can be administered an effective amount of at least one nitric oxide enhancing diuretic compound and at least one nitric oxide enhancing compound. In yet another embodiment, the patient has an effective amount of at least one nitric oxide-enhancing diuretic compound and, for example, an aldosterone antagonist, an α-adrenergic receptor antagonist, an angiotensin II antagonist, an angiotensin converting enzyme (ACE) inhibitor, an antidiabetic Compounds, antihyperlipidemic compounds, antioxidants, antithrombotic and vasodilatory compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H ₂ receptor antagonists , Neutral endopeptidase inhibitors, non-steroidal anti-inflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, thrombocytopenia, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) Inhibitor Beauty including like these two or more combinations are not limited to, can be administered and at least one therapeutic agent. In another embodiment, the patient can be administered an effective amount of at least one nitric oxide enhancing diuretic compound, at least one therapeutic agent, and at least one nitric oxide enhancing compound. In one embodiment, the condition resulting from overhydration and / or electrolyte retention is lower limb swelling, fatigue, fluid retention, cardiac hypertrophy and / or edema. The nitric oxide enhancing diuretic compound, the nitric oxide enhancing compound, and / or the therapeutic agent can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.

The present invention provides a method of treating cardiovascular disorders by administering an effective amount of a compound and / or composition described herein to a patient in need thereof. For example, the patient can be administered an effective amount of at least one nitric oxide-enhancing diuretic compound. In another embodiment, the patient can be administered an effective amount of at least one nitric oxide enhancing diuretic compound and at least one nitric oxide enhancing compound. In another aspect, the patient has an effective amount of at least one nitric oxide-enhancing diuretic compound and, for example, an aldosterone antagonist, an α-adrenergic receptor antagonist, an angiotensin II antagonist, an angiotensin converting enzyme (ACE) inhibitor, an antidiabetic compound. Antihyperlipidemic compounds, antioxidants, antithrombotic and vasodilatory compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H ₂ receptor antagonists, Neutral endopeptidase inhibitors, non-steroidal anti-inflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, thrombocytopenic agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibition Agent and this Including such combinations of two or more of al, but not limited to, it can be administered and at least one therapeutic agent. In another embodiment, the patient can be administered an effective amount of at least one nitric oxide enhancing diuretic compound, at least one therapeutic agent, and at least one nitric oxide enhancing compound. In one embodiment, the cardiovascular disorder is hypertension, heart failure and / or diastolic dysfunction. The nitric oxide enhancing diuretic compound, the nitric oxide enhancing compound, and / or the therapeutic agent can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.

The present invention provides a method of treating renovascular disease by administering an effective amount of a compound and / or composition described herein to a patient in need thereof. For example, the patient can be administered an effective amount of at least one nitric oxide-enhancing diuretic compound. In another embodiment, the patient can be administered an effective amount of at least one nitric oxide enhancing diuretic compound and at least one nitric oxide enhancing compound. In another aspect, the patient has an effective amount of at least one nitric oxide-enhancing diuretic compound and, for example, an aldosterone antagonist, an α-adrenergic receptor antagonist, an angiotensin II antagonist, an angiotensin converting enzyme (ACE) inhibitor, an antidiabetic compound. Antihyperlipidemic compounds, antioxidants, antithrombotic and vasodilatory compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H ₂ receptor antagonists, Neutral endopeptidase inhibitors, non-steroidal anti-inflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, thrombocytopenic agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibition Agent and this Including such combinations of two or more of al, but not limited to, it can be administered and at least one therapeutic agent. In another embodiment, the patient can be administered an effective amount of at least one nitric oxide enhancing diuretic compound, at least one therapeutic agent, and at least one nitric oxide enhancing compound. In one embodiment, the renovascular disease is renal failure, renal dysfunction, renal alteration associated with severe hypertension or renovascular hypertension. The nitric oxide enhancing diuretic compound, the nitric oxide enhancing compound, and / or the therapeutic agent can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.

The present invention treats diabetes by administering an effective amount of a compound and / or composition described herein to a patient in need thereof; treats a disease resulting from oxidative stress; endothelial dysfunction Treat diseases caused by endothelial dysfunction; treat cirrhosis; treat preeclampsia; treat osteoporosis; treat nephropathy; treat peripheral vascular disease; portal hypertension A method for treating central nervous system disorders; treating metabolic syndrome; treating sexual dysfunction; and a method for treating hyperlipidemia. For example, the patient can be administered an effective amount of at least one nitric oxide-enhancing diuretic compound. In another embodiment, the patient can be administered an effective amount of at least one nitric oxide enhancing diuretic compound and at least one nitric oxide enhancing compound. Further, in another aspect, the patient has an effective amount of at least one nitric oxide-enhancing diuretic compound and, for example, an aldosterone antagonist, an α-adrenergic receptor antagonist, an angiotensin II antagonist, an angiotensin converting enzyme (ACE) inhibitor, Diabetic compounds, antihyperlipidemic compounds, antioxidants, antithrombotic and vasodilatory compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H ₂ receptors Antagonists, neutral endopeptidase inhibitors, non-steroidal anti-inflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, thrombocytopenic agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2 ) Inhibitors, And including like these two or more combinations are not limited to, it can be administered and at least one therapeutic agent. In another embodiment, the patient can be administered an effective amount of at least one nitric oxide enhancing diuretic compound, at least one therapeutic agent, and at least one nitric oxide enhancing compound. The nitric oxide enhancing diuretic compound, the nitric oxide enhancing compound, and / or the therapeutic agent can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.

  When administered separately, the nitric oxide-enhancing diuretic compound, nitric oxide-enhancing compound and / or therapeutic agent can be administered as part of the overall treatment regimen, ie at about the same time as a combination therapy. “About the same time” means that at least one nitric oxide-enhancing diuretic compound is administered simultaneously, sequentially, at the same time, as long as they are administered as part of the overall treatment plan, ie, as a combination therapy or treatment cocktail. Including administration at different times on the same day or on different days.

  When administered in vivo, the compounds and compositions of the invention can be administered in combination with pharmaceutically acceptable carriers and at the dosages described herein. When the compounds and compositions of the invention are administered as a combination of at least one nitric oxide enhancing diuretic compound and / or at least one nitric oxide enhancing compound and / or therapeutic agent, they are also identified as therapeutic targets Can be used in combination with one or more additional compounds known to be effective in other disease states. Nitric oxide enhancing compounds, therapeutic agents and / or other additional compounds can be administered simultaneously with, subsequent to, or prior to administration of the nitric oxide enhancing diuretic compound.

  The compounds and compositions of the present invention can be administered orally, buccally, parenterally in unit dosage forms optionally containing conventional pharmaceutically acceptable non-toxic carriers, adjuvants and excipients. Administer by any available and effective delivery system including, but not limited to, by inhalation, by topical application, by injection, transdermally, or rectally (e.g., by use of suppositories) be able to. Parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In one embodiment of the invention, the nitric oxide enhancing diuretic compound is administered orally, parenterally or by inhalation.

  Administration of a transdermal compound known to those skilled in the art involves the delivery of a pharmaceutical compound that is infused into the systemic circulation of the patient via the transdermal passage of the compound. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. Other ingredients can also be incorporated into the transdermal patch. For example, formulating compositions and / or transdermal patches with one or more preservatives or antimicrobial agents including but not limited to methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, and the like can do. Dosage forms for topical administration of the compounds and compositions of the present invention can include creams, sprays, lotions, gels, ointments, eye drops, nasal drops, ear drops and the like. In such dosage forms, the composition of the present invention is mixed with, for example, 1% or 2% (wt / wt) benzyl alcohol as a preservative, emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water and sorbitol solution. A white, smooth, uniform, opaque cream or lotion can then be formed. In addition, the composition of the present invention may contain polyethylene glycol 400. Mix them with, for example, 2% (wt / wt) benzyl alcohol, white petrolatum, emulsifying wax and tenox II (butylhydroxyanisole, propyl gallate, citric acid, propylene glycol) as preservatives to make an ointment. Can be formed. A woven pad or roll dressing, such as gauze, may be impregnated with the composition of the invention in the form of a solution, lotion, cream, ointment, or other such forms are used for topical application. Also good. The composition of the present invention can be applied topically using a transdermal system such as one of acrylic polymer adhesives impregnated with a resinous crosslinker with the composition of the present invention and laminated to an impermeable backing. Can also be applied.

  The composition of the present invention can be applied topically using a transdermal system such as one of the acrylic polymer adhesives infiltrated with a resinous crosslinker with the composition of the present invention and laminated to an impermeable backing. It can also be applied to. In certain embodiments, the compositions of the invention are administered as a transdermal patch, more specifically as a sustained release transdermal patch. The transdermal patch of the present invention can comprise any conventional one, such as, for example, an adhesive matrix, a polymer matrix, a storage patch, a matrix or a monolithic laminated structure, and typically has one or more backings It consists of a layer, an adhesive, a penetration enhancer, an optional rate controlling membrane and a release liner that is removed to expose the adhesive prior to application. The polymer matrix patch also includes a polymer matrix molding material. Suitable transdermal patches are described in detail, for example, in U.S. Patent Nos. 5,262,165, 5,948,433, 6,010,715, and 6,071,531, the disclosures of each of which are hereby incorporated in their entirety. Is incorporated into.

  Solid dosage forms for oral administration include capsules, sustained release capsules, tablets, sustained release tablets, chewing tablets, sublingual tablets, effervescent tablets, chewable tablets, pills, powders, sachets, granules and gels Can be mentioned. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms can usually contain additional materials other than inert diluents, for example lubricants such as magnesium stearate. In the case of capsules, tablets, effervescent tablets, and pills, the dosage forms can contain buffering agents. Soft gelatin capsules may be formulated to contain a mixture of the active compound or composition of the present invention and vegetable oil. Hard gelatin capsules may contain granules of the active compounds of the invention in combination with a solid powder carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives of gelatin and the like. Tablets and pills can be formulated with enteric coatings.

  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents such as water commonly used in the art. Can do. Such compositions can also contain wetting agents, emulsifying and suspending agents and adjuvants such as sweetening, flavoring and perfuming agents.

  Suppositories for vaginal or rectal administration of the compounds and compositions of the present invention are solid at room temperature and liquid at rectal temperature so that the compounds or compositions of the present invention melt in the rectum to release the drug. Can be formulated by mixing with suitable nonirritating excipients such as cocoa butter and polyethylene glycol.

  Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing agents, wetting agents and / or suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. Sterile fixed oils are also conventionally used as a solvent or suspending medium.

  The compositions of the present invention can further comprise conventional excipients, ie pharmaceutically acceptable organic or inorganic carrier materials suitable for parenteral application that do not deleteriously react with the active compounds of the present invention. . Examples of suitable pharmaceutically acceptable carriers include water, salt solution, alcohol, vegetable oil, polyethylene glycol, gelatin, lactose, amylose, magnesium stearate, talc, surfactant, silicic acid, viscous paraffin, aromatic oil, Examples include fatty acid monoglycerides, fatty acid diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, and polyvinylpyrrolidone. Pharmaceutical formulations are sterilized and, where appropriate, adjuvants that do not adversely react with the active compound, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, flavoring agents. And / or can be mixed with aromatic substances and the like. Excipients that are particularly suitable for parenteral application preferably consist of oily or aqueous solutions and suspensions, emulsions or implants. Aqueous suspensions can contain substances that increase the viscosity of the suspension and include, for example, sodium carboxymethylcellulose, sorbitol, and / or dextran. Optionally, the suspending agent can also contain a stabilizer.

  The composition can also optionally contain minor amounts of wetting agents, emulsifying agents, and / or pH buffering agents. The composition of the present invention may be a solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The composition of the present invention can be formulated as a suppository, containing traditional binders and carriers such as triglycerides. Oral formulations can include standard carriers such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate.

  Various delivery systems are known, including, for example, encapsulation in liposomes, microbubbles, emulsions, microparticles, microcapsules, and the like, and can be used to administer a compound or composition of the invention. The required dose can be administered as a single dosage unit or as a sustained release dosage form.

  The bioavailability of the compositions of the present invention is that the formulation is micronized using conventional techniques such as grinding, milling, spray drying, etc. in the presence of suitable excipients or substances such as phospholipids or surfactants. Can be increased.

  The sustained release dosage form of the present invention may include microparticles and / or nanoparticles having a therapeutic agent dispersed therein, or may include a pure, preferably crystalline, solid therapeutic agent. . For sustained release administration, microcrystalline dosage forms containing pure, crystalline, therapeutic agents are preferred. The therapeutic dosage form of this aspect of the invention may be of any shape suitable for sustained release.

  The nanoparticle sustained release therapeutic dosage form is preferably biodegradable and optionally binds to vascular smooth muscle cells and first enters these cells by eating and drinking action. Biodegradation of nanoparticles occurs over time in prelysosomal vesicles and lysosomes (eg, 30 to 120 days; or 10 to 21 days). The larger microparticle therapeutic dosage form of the present invention releases the therapeutic agent for subsequent target cell uptake with only some of the smaller microparticles entering the cell by phagocytosis. One skilled in the art will recognize that the precise mechanism by which target cells assimilate and metabolize the dosage form of the present invention depends on the morphology, physiology, and metabolic processes of these cells. The size of the sustained release therapeutic dosage form is also important with respect to the cellular anabolic mode. For example, the smaller nanoparticles can flow between cells with the interstitial fluid and penetrate into the infused tissue. The larger microparticles tend to be more easily trapped in the interstitium within the infused primary tissue and are thus useful for delivering antiproliferative therapeutics.

  Certain sustained release dosage forms of the present invention include biodegradable microparticles or nanoparticles. More specifically, the biodegradable microparticles or nanoparticles are formed of a polymer that contains a matrix that biodegrades by random non-enzymatic hydrolytic cleavage that releases the therapeutic agent and thus forms pores within the particulate structure. The

  In certain embodiments, the compositions of the invention are administered orally as sustained release tablets or sustained release capsules. For example, the sustained release formulation can comprise an effective amount of at least one nitric oxide enhancing diuretic compound or a pharmaceutically acceptable salt thereof, and optionally at least one nitric oxide donor, or the sustained release. The sex preparation can comprise an effective amount of at least one nitric oxide enhancing diuretic compound or a pharmaceutically acceptable salt thereof, at least one nitric oxide donor, and optionally at least one therapeutic agent.

  The compounds and compositions of the invention can be formulated as pharmaceutically acceptable salt forms. Examples of pharmaceutically acceptable salts include alkali metal salts and free acids, or addition salts of free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of such inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acids include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid , Glutamic acid, benzoic acid, anthranilic acid, mesylic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfone Acids, 2-hydroxyethanesulfonic acid, sulfanilic acid, stearic acid, alginic acid, β-hydroxybutyric acid, cyclohexylaminosulfonic acid, galactaric acid and galacturonic acid, aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic acid And organic acids such as sulfonic acids It is not limited to these examples. Suitable pharmaceutically acceptable base addition salts include metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or primary, secondary, and tertiary amines, cyclic amines, N, Examples include, but are not limited to, organic salts made from N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, and the like. All of these salts can be prepared by conventional means from the corresponding compound, for example, by reacting the appropriate acid or base with the compound of the invention. In one embodiment, the pharmaceutically acceptable salt of the compound of the invention comprises a nitrate.

  While individual requirements may vary, setting an optimal range of effective amounts of the compounds and / or compositions of the invention is within the skill of the art. In general, the dose required to provide an effective amount of the compounds and compositions of the invention that can be adjusted by those skilled in the art is the age, health, physical condition, sex, diet, weight, dysfunction of the recipient. Extent of treatment, frequency of treatment, and dysfunction or disease of the patient, nature and extent of the medical condition, route of administration, activity, effect, pharmacokinetic and toxicity profile of the particular compound used, whether to use a drug delivery system It depends on whether the compound of the invention is administered as part of a drug combination.

  The amount of a given nitric oxide-enhancing diuretic compound that can be effective in the treatment of a particular disease or condition depends on the nature of the disease or condition and is described in Goodman and Gilman, supra; The Physician's Desk Reference, Medical Economics Company, Inc. , Oradell, NJ, 1995; and Drug Facts and Comparisons, Inc., St. Louis, MO, 1993. The exact dosage used in the formulation will also depend on the route of administration and the severity of the disease or disorder and should be determined by the physician and patient's circumstances.

The present invention also relates to pharmaceutical compounds of the invention and / or comprising at least one or more novel nitric oxide enhancing diuretic compounds and one or more nitric oxide enhancing compounds described herein. A pharmaceutical kit is provided comprising one or more containers filled with one or more components of the composition. Further therapeutic agents or compositions (e.g., aldosterone antagonists, α-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin converting enzyme (ACE) inhibitors, antidiabetic compounds, antihyperlipidemic compounds, antioxidants, Thrombotic and vasodilatory compounds, β-adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H ₂ receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal anti-inflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel blockers, thrombocytopenic agents, proton pump inhibitors, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of two or more of these ),That This form of notification is in the form prescribed by governmental authorities that regulate the manufacture, use or sale of drugs or biological products that reflect the approval of the authorities for the manufacture, use or sale of humans, and the device to administer the composition. May accompany a small kit.

6-ブロモヘキサン-1-オール(10 g, 55.2 mmol)をアセトニトリル(200 mL)に溶解した。この溶液に硝酸銀(12.19 g, 71.76 mmol, 1.3当量)を加え、反応混合物を窒素雰囲気下で2時間還流した。ろ過による固形物の除去後、溶媒を減圧下で蒸発させた。残留物を酢酸エチルで抽出し、次に水、塩水で洗浄し、硫酸ナトリウムで乾燥し、シリカゲルの小パッドを通してろ過し、次に減圧下で蒸発させて、表題の化合物を黄白色の油状物(8.28 g, 収率92%)として得た。

Examples Example 1: 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [5- (nitrooxy) pentyl]-, 1,1- Dioxide
1a 1,6-hexanediol, mononitrate

6-Bromohexane-1-ol (10 g, 55.2 mmol) was dissolved in acetonitrile (200 mL). To this solution was added silver nitrate (12.19 g, 71.76 mmol, 1.3 eq) and the reaction mixture was refluxed for 2 hours under a nitrogen atmosphere. After removal of solids by filtration, the solvent was evaporated under reduced pressure. The residue is extracted with ethyl acetate, then washed with water, brine, dried over sodium sulfate, filtered through a small pad of silica gel and then evaporated under reduced pressure to afford the title compound as a pale yellow oil (8.28 g, 92% yield).

実施例1aの生成物(8.19 g, 42 mmol)をジクロロメタン(200 mL)に溶解した。この溶液にDess-Martinペルヨージナン試薬(Lancaster Synthesis, 17.8 g, 42 mmol)、引き続いて水(0.8 mL)を連続的に加え、反応混合物を室温で2時間撹拌した。固形沈殿物をろ去し、ろ液を硫酸ナトリウムで乾燥し、次にシリカゲルのパッドを通してろ過し、次に減圧で蒸発させて、ほぼ定量的な収率の表題の化合物を得た。

1b. Hexanal, 6- (nitrooxy)-

The product of Example 1a (8.19 g, 42 mmol) was dissolved in dichloromethane (200 mL). To this solution was added Dess-Martin periodinane reagent (Lancaster Synthesis, 17.8 g, 42 mmol) followed by water (0.8 mL) and the reaction mixture was stirred at room temperature for 2 hours. The solid precipitate was filtered off and the filtrate was dried over sodium sulfate, then filtered through a pad of silica gel and then evaporated under reduced pressure to give an almost quantitative yield of the title compound.

実施例1bの粗生成物(42 mmol)および2-アミノ-6-クロロ-1,3-ベンゼンジスルホンアミド(Aldrich Chemical Co., 10.85 g, 38 mmol)をジオキサン(300 mL)および濃塩酸(9 mL)の中で一緒に混合した。反応混合物を1時間還流した。次いで、これを室温に冷却し、飽和塩水で洗浄し、次に有機層を分離し、溶媒を減圧で蒸発させた。得られた残留物を酢酸エチルで処理し、炭酸ナトリウム飽和水溶液、水、塩水で洗浄し、硫酸ナトリウムで乾燥し、ろ過し、ろ液を真空で濃縮して粗生成物を得た。シリカゲルのカラムクロマトグラフィーでの精製により、4%メタノールのジクロロメタン液で溶出させて油状物(7.7 g)を得、これを20%酢酸エチルのヘキサン液で摩砕して、表題の化合物(6.7 g, 収率41%)を白色の固形物として得た: mp 158-161℃;

質量スペクトル(API-TIS) m/z 429 (MH)⁺, 446 (MNH₄)⁺。 1c. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [5- (nitrooxy) pentyl]-, 1,1-dioxide

The crude product of Example 1b (42 mmol) and 2-amino-6-chloro-1,3-benzenedisulfonamide (Aldrich Chemical Co., 10.85 g, 38 mmol) were added to dioxane (300 mL) and concentrated hydrochloric acid (9 mixed together in mL). The reaction mixture was refluxed for 1 hour. It was then cooled to room temperature and washed with saturated brine, then the organic layer was separated and the solvent was evaporated under reduced pressure. The resulting residue was treated with ethyl acetate, washed with saturated aqueous sodium carbonate, water, brine, dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give a crude product. Purification by column chromatography on silica gel eluting with 4% methanol in dichloromethane gave an oil (7.7 g) which was triturated with 20% ethyl acetate in hexane to give the title compound (6.7 g , Yield 41%) as a white solid: mp 158-161 ° C;

Mass spectrum (API-TIS) m / z 429 (MH) ⁺ , 446 (MNH ₄ ) ⁺ .

表題の化合物を実施例1cに記載されている手順に従って実施例1bの生成物(5 mmol)および2-アミノ-6-(トリフルオロメチル)-1,3-ベンゼンジスルホンアミド(Fluka chemicals, 1.6 g, 5 mmol)の反応により調製した。表題の化合物を白色の固形物(0.95 g, 収率41%)として得た: mp 171-189℃;

質量スペクトル(API-TIS) m/z 463 (MH)⁺, 480 (MNH₄)⁺。 Example 2: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- [5- (nitrooxy) pentyl] -6- (trifluoromethyl)-, 1, 1-dioxide

The title compound was prepared according to the procedure described in Example 1c (5 mmol) and 2-amino-6- (trifluoromethyl) -1,3-benzenedisulfonamide (Fluka chemicals, 1.6 g , 5 mmol) reaction. The title compound was obtained as a white solid (0.95 g, 41% yield): mp 171-189 ° C .;

Mass spectrum (API-TIS) m / z 463 (MH) ⁺ , 480 (MNH ₄ ) ⁺ .

硝酸銀(7.87 g, 46.3 mmol)および酢酸4-ブロモブチル(4.40 g, 22.6 mmol)のアセトニトリル(100 mL)溶液を室温で一晩、その後70℃でさらに1時間撹拌した。混合物を室温に冷却し、次に塩水(150 mL)とともに1時間撹拌した。得られた混合物をセライト(Celite)を通してろ過し、アセトニトリルで洗浄した。ろ液を濃縮し、次に酢酸エチル(50 mL×2)で抽出した。合わせた有機抽出液を水および塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮し、真空下で乾燥させて表題の化合物を黄色の油状物(3.58 g, 収率89%)として得た。NMR分析から純度が95%を超える、この生成物をさらには精製せずに次の段階で用いた。

Example 3: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- [3- (nitrooxy) propyl] -6- (trifluoromethyl)-, 1, 1-dioxide
3a. 1,4-Butanediol, acetate nitrate

A solution of silver nitrate (7.87 g, 46.3 mmol) and 4-bromobutyl acetate (4.40 g, 22.6 mmol) in acetonitrile (100 mL) was stirred at room temperature overnight and then at 70 ° C. for an additional hour. The mixture was cooled to room temperature and then stirred with brine (150 mL) for 1 hour. The resulting mixture was filtered through Celite and washed with acetonitrile. The filtrate was concentrated and then extracted with ethyl acetate (50 mL × 2). The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered, concentrated and dried under vacuum to give the title compound as a yellow oil (3.58 g, 89% yield) Got as. This product, purity> 95% from NMR analysis, was used in the next step without further purification.

実施例3aの粗生成物(1.03 g, 5.8 mmol)および2 N NaOH (2.6 mL, 5.2 mmol)のMeOH (20 mL)液を室温で2時間撹拌した。反応混合物を3 N HClで酸性化し、次に減圧下で濃縮した。残留物を3 N HClとCH₂Cl₂との間で分配した。有機抽出液を水および塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮し、真空下で乾燥させて表題の化合物を黄色の油状物(0.47 g, 収率70%)として得た。NMR分析から純度が95%を超える、この生成物を精製せずに次の段階で用いた。

3b. 1,4-Butanediol, mononitrate

A solution of the crude product of Example 3a (1.03 g, 5.8 mmol) and 2 N NaOH (2.6 mL, 5.2 mmol) in MeOH (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was acidified with 3 N HCl and then concentrated under reduced pressure. The residue was partitioned between 3 N HCl and CH ₂ Cl ₂ . The organic extract was washed with water and brine, dried over Na ₂ SO ₄ , filtered, concentrated, and dried under vacuum to give the title compound as a yellow oil (0.47 g, 70% yield). It was. This product, which was> 95% pure from NMR analysis, was used in the next step without purification.

実施例3bの生成物(0.33 g, 2 mmol)を実施例1bの手順に従いジクロロメタン(10 mL)中Dess-Martinペルヨージナン試薬(0.85 g, 2 mmol)および水(50 μL)で処理して、ほぼ定量的な収率の表題の化合物を得た。得られた粗生成物をさらには精製せずに次の段階でそのまま用いた。 3c. Butanal, 4- (Nitrooxy)-

Treat the product of Example 3b (0.33 g, 2 mmol) with Dess-Martin periodinane reagent (0.85 g, 2 mmol) and water (50 μL) in dichloromethane (10 mL) according to the procedure of Example 1b. A quantitative yield of the title compound was obtained. The resulting crude product was used directly in the next step without further purification.

実施例3cの生成物(2 mmol)を実施例1cの手順に従ってジオキサン(20 mL)に溶解し、2-アミノ-6-(トリフルオロメチル)-1,3-ベンゼンジスルホンアミド(0.64 g, 2 mmol)および濃塩酸(0.4 mL)で処理した。生成物をシリカゲルフラッシュクロマトグラフィーにより3%メタノールのジクロロメタン液で溶出させて精製し、表題の化合物(0.54 g, 収率62%)を白色の固形物として得た: mp 165℃ (分解);

質量スペクトル(API-TIS) m/z 435 (MH)⁺, 452 (MNH₄)⁺。 3d. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- [3- (nitrooxy) propyl] -6- (trifluoromethyl)-, 1,1- Dioxide

The product of Example 3c (2 mmol) was dissolved in dioxane (20 mL) according to the procedure of Example 1c and 2-amino-6- (trifluoromethyl) -1,3-benzenedisulfonamide (0.64 g, 2 mmol) and concentrated hydrochloric acid (0.4 mL). The product was purified by silica gel flash chromatography eluting with 3% methanol in dichloromethane to give the title compound (0.54 g, 62% yield) as a white solid: mp 165 ° C. (decomposition);

Mass spectrum (API-TIS) m / z 435 (MH) ⁺ , 452 (MNH ₄ ) ⁺ .

AgNO₃ (14 g, 82.8 mmol)を5-ブロモ吉草酸(10 g, 55 mmol)のアセトニトリル(70 mL)溶液に加えた。反応混合物を室温で2日間撹拌した。ろ過および蒸発後の残留物をシリカゲルのクロマトグラフィーにより分離しEtOAc:ヘキサン(1:1)で溶出させて、表題の化合物(8 g, 収率89%)を無色の油状物として得た。

質量スペクトル(API-TIS) m/z 181 (MNH₄)⁺。 Example 4: Pentanamide, N- [7- (aminosulfonyl) -6-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] -5- (nitrooxy) -
4a. Pentanoic acid, 5- (nitrooxy)-

AgNO ₃ (14 g, 82.8 mmol) was added to a solution of 5-bromovaleric acid (10 g, 55 mmol) in acetonitrile (70 mL). The reaction mixture was stirred at room temperature for 2 days. The residue after filtration and evaporation was separated by chromatography on silica gel and eluted with EtOAc: hexane (1: 1) to give the title compound (8 g, 89% yield) as a colorless oil.

Mass spectrum (API-TIS) m / z 181 (MNH ₄ ) ⁺ .

表題の化合物を英国特許第847,176号の手順に従うことにより、4-クロロ-6-アミノベンゼン-1,3-ジスルホンアミド(10 g, 35 mmol)および炭酸グアニジン(5 g, 28 mmol)を用いて合成した。白色の固形物を得た(0.9 g): mp >260℃;

質量スペクトル(API-TIS) m/z 311 (MH)⁺。C₇H₇ClN₄O₄S₂に対し算出された分析値: C, 27.06; H, 2.27; N, 18.03; Cl, 11.41。実測値: C, 26.75; H, 2.38; N, 18.15; Cl, 11.37。 4b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3-amino-6-chloro-, 1,1-dioxide

By following the procedure of British Patent No. 847,176 using the title compound with 4-chloro-6-aminobenzene-1,3-disulfonamide (10 g, 35 mmol) and guanidine carbonate (5 g, 28 mmol). Synthesized. A white solid was obtained (0.9 g): mp> 260 ° C;

Mass spectrum (API-TIS) m / z 311 (MH) ⁺ . _{C 7 H 7 ClN 4 O 4} S 2 calculated analytical values for: C, 27.06; H, 2.27 ; N, 18.03; Cl, 11.41. Found: C, 26.75; H, 2.38; N, 18.15; Cl, 11.37.

0℃で実施例4bの生成物(0.25 g, 0.8 mmol)、実施例4aの生成物(0.13 g, 0.8 mmol)およびN,N-ジメチルアミノピリジン(DMAP, 98 mg, 0.8 mmol)のDMF (2 mL)混合物を1-(3-(ジメチルアミノ)プロピル)-3-エチルカルボジイミド塩酸塩(0.19 g, 1 mmol)で処理した。反応混合物を室温で16時間撹拌した。溶媒の蒸発後の残留物をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:EtOAc:MeOH (1:1:0.1)〜CH₂Cl₂:MeOH (1:0.5)で溶出させて、表題の化合物(0.1 g, 収率27%)を白色の固形物として得た: mp 222-225℃;

質量スペクトル(API-TIS) m/z 454 (M-H)。 4c. Pentanamide, N- [7- (aminosulfonyl) -6-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] -5- (nitrooxy)-

DMF of the product of Example 4b (0.25 g, 0.8 mmol), the product of Example 4a (0.13 g, 0.8 mmol) and N, N-dimethylaminopyridine (DMAP, 98 mg, 0.8 mmol) (2 mL) The mixture was treated with 1- (3- (dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (0.19 g, 1 mmol). The reaction mixture was stirred at room temperature for 16 hours. The residue after evaporation of the solvent is separated by chromatography on silica gel and eluted with CH ₂ Cl ₂ : EtOAc: MeOH (1: 1: 0.1) to CH ₂ Cl ₂ : MeOH (1: 0.5) to give the title compound (0.1 g, 27% yield) was obtained as a white solid: mp 222-225 ° C .;

Mass spectrum (API-TIS) m / z 454 (MH).

AgNO₃ (13 g, 76.9 mmol)を6-ブロモヘキサン酸(10 g, 51 mmol)のアセトニトリル(50 mL)溶液に加えた。反応混合物を室温で2日間撹拌した。ろ過および蒸発後の残留物をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:EtOAc (1:1)で溶出させて、表題の化合物(9 g, 収率99%)を低融点の固形物として得た。

質量スペクトル(API-TIS) m/z 177 (M⁺)。 Example 5: Hexanamide, N- [7- (aminosulfonyl) -6-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] -6- (nitrooxy) -
5a hexanoic acid, 6- (nitrooxy)-

AgNO ₃ (13 g, 76.9 mmol) was added to a solution of 6-bromohexanoic acid (10 g, 51 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at room temperature for 2 days. The residue after filtration and evaporation was separated by chromatography on silica gel and eluted with CH ₂ Cl ₂ : EtOAc (1: 1) to give the title compound (9 g, 99% yield) as a low melting solid. Obtained.

Mass spectrum (API-TIS) m / z 177 (M ⁺ ).

表題の化合物を実施例4cの手順に従うことにより、DMF (2 mL)中の実施例4bの生成物(0.25 g, 0.8 mmol)、実施例5aの生成物(0.19 g, 1.1 mmol)、N,N-ジメチルアミノピリジン(DMAP, 98 mg, 0.8 mmol)および1-(3-(ジメチルアミノ)プロピル)-3-エチルカルボジイミド塩酸塩(0.19 g, 1 mmol)から白色の固形物(0.1 g, 収率26%)として調製した: Mp 177-179℃;

質量スペクトル(API-TIS) m/z 470 (MH⁺)、487 (MNH₄ ⁺)。 5b. Hexanamide, N- [7- (aminosulfonyl) -6-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] -6- (nitrooxy)-

By following the procedure of Example 4c for the title compound, the product of Example 4b (0.25 g, 0.8 mmol), the product of Example 5a (0.19 g, 1.1 mmol) in DMF (2 mL), N, White solid (0.1 g, yield) from N-dimethylaminopyridine (DMAP, 98 mg, 0.8 mmol) and 1- (3- (dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (0.19 g, 1 mmol). Rate 26%): Mp 177-179 ° C;

Mass spectrum (API-TIS) m / z 470 (MH ⁺ ), 487 (MNH ₄ ⁺ ).

4,5-ビス(ニトロオキシ)ペンタン-1-オールを国際公開公報第2005/030135 A2号に記載されている手順(実施例27d)に従うことにより5 mmolスケールで調製した。生成物を実施例1bに記載されている手順に従い、Dess-Martinペルヨージナン試薬を用いて酸化した。得られた粗生成物をさらには精製せずに用いた。

Example 6: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3- [3,4-bis (nitrooxy) butyl] -6-chloro-3,4-dihydro-, 1,1 -Dioxide
6a. Pentanal, 4,5-bis (nitrooxy)-

4,5-bis (nitrooxy) pentan-1-ol was prepared on a 5 mmol scale by following the procedure described in WO 2005/030135 A2 (Example 27d). The product was oxidized using Dess-Martin periodinane reagent according to the procedure described in Example 1b. The resulting crude product was used without further purification.

実施例6aの生成物(2.5 mmol)を実施例1cの手順に従って、ジオキサン(25 mL)に溶解し、2-アミノ-6-クロロ-1,3-ベンゼンジスルホンアミド(0.64 g, 2 mmol)および塩酸(0.5 mL)で処理した。得られた生成物をシリカゲルフラッシュクロマトグラフィーにより3%メタノールのジクロロメタン液で溶出させて精製し、表題の化合物を油状物として得、これを酢酸エチル/ヘキサン(40:60)から再結晶して、純粋な生成物を白色の固形物(0.780 g)として収率82%で得た:mp 153-155℃;

質量スペクトル(API-TIS) m/z 493 (MNH₄)⁺。 6b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- [3,4-bis (nitrooxy) butyl] -6-chloro-3,4-dihydro-, 1,1-dioxide

The product of Example 6a (2.5 mmol) was dissolved in dioxane (25 mL) according to the procedure of Example 1c and 2-amino-6-chloro-1,3-benzenedisulfonamide (0.64 g, 2 mmol) and Treated with hydrochloric acid (0.5 mL). The resulting product was purified by silica gel flash chromatography eluting with 3% methanol in dichloromethane to give the title compound as an oil which was recrystallized from ethyl acetate / hexane (40:60) The pure product was obtained as a white solid (0.780 g) in 82% yield: mp 153-155 ° C .;

Mass spectrum (API-TIS) m / z 493 (MNH ₄ ) ⁺ .

実施例6aの生成物(2.5 mmol)を実施例1cの手順に従って、ジオキサン(25 mL)に溶解し、2-アミノ-6-(トリフルオロメチル)-1,3-ベンゼンジスルホンアミド(0.64 g, 2 mmol)および濃塩酸(0.5 mL)で処理した。生成物をシリカゲルフラッシュクロマトグラフィーにより3%メタノールのジクロロメタン液で溶出させて精製し、表題の化合物を油状物として得、これを酢酸エチル/ヘキサン(40:60)から再結晶して、純粋な生成物を白色の固形物(0.75 g, 収率74%)として得た: mp 157-160℃(分解);

質量スペクトル(API-TIS) m/z 527 (MNH₄)⁺。 Example 7: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3- [3,4-bis (nitrooxy) butyl] -3,4-dihydro-6- (trifluoromethyl)- 1,1-dioxide

The product of Example 6a (2.5 mmol) was dissolved in dioxane (25 mL) according to the procedure of Example 1c and 2-amino-6- (trifluoromethyl) -1,3-benzenedisulfonamide (0.64 g, 2 mmol) and concentrated hydrochloric acid (0.5 mL). The product was purified by silica gel flash chromatography eluting with 3% methanol in dichloromethane to give the title compound as an oil which was recrystallized from ethyl acetate / hexane (40:60) to give pure product. Product was obtained as a white solid (0.75 g, 74% yield): mp 157-160 ° C. (decomposition);

Mass spectrum (API-TIS) m / z 527 (MNH ₄ ) ⁺ .

表題の化合物を実施例1cの手順に従って、実施例3cの生成物(2.5 mmol)および2-アミノ-6-クロロ-1,3-ベンゼンジスルホンアミド(0.57 g, 2 mmol)から調製した。表題の化合物を白色の固形物(0.49 g, 収率61%)として得た: mp 178-181℃;

質量スペクトル(API-TIS) m/z 401(MH)⁺、403 [(MH) + 2]⁺、418 (MNH₄)⁺、420 [(MNH₄) + 2]⁺。 Example 8: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [3- (nitrooxy) propyl]-, 1,1-dioxide

The title compound was prepared from the product of Example 3c (2.5 mmol) and 2-amino-6-chloro-1,3-benzenedisulfonamide (0.57 g, 2 mmol) according to the procedure of Example 1c. The title compound was obtained as a white solid (0.49 g, 61% yield): mp 178-181 ° C .;

Mass spectrum (API-TIS) m / z 401 (MH) ⁺ , 403 [(MH) + 2] ⁺ , 418 (MNH ₄ ) ⁺ , 420 [(MNH ₄ ) + 2] ⁺ .

この表題の化合物をFruttero et al, J. Heterocyclic Chem., 26: 1345-1347 (1989)に記載されているように合成した。低融点の固形物。

質量スペクトル(API-TIS) m/z 127 (M-H)。 Example 9: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- (4-methyl-5-oxide-1,2,5-oxa Diazol-3-yl)-, 1,1-dioxide
9a. 1,2,5-oxadiazole-3-carboxaldehyde, 4-methyl-, 5-oxide

The title compound was synthesized as described in Fruttero et al, J. Heterocyclic Chem., 26: 1345-1347 (1989). Low melting solid.

Mass spectrum (API-TIS) m / z 127 (MH).

4-クロロ-6-アミノベンゼン-1,3-ジスルホンアミド(0.3 g, 1.05 mmol)および実施例9aの生成物(0.23 g, 1.8 mmol)のジオキサン(9 mL)混合物に、濃HCl (1 mL)を滴下した。反応混合物を60℃で1時間加熱し、次いで室温に冷却した。粗反応混合物をシリカゲルのクロマトグラフィーにより分離しMeOH:CH₂Cl₂ (0.5:9.5〜1:9〜1.5:8.5)で溶出させて、表題の化合物(0.24 g, 収率58%)を白色の固形物として得た: mp 242-243℃ (分解);

質量スペクトル(API-TIS) m/z 394 (M-H)、413 (MNH₄ ⁺)。C₁₀H₁₀ClN₅O₆S₂に対し算出された分析値: C, 30.34; H, 2.55; N, 17.69。実測値: C, 30.25; H, 2.49; N, 17.42。 9b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- (4-methyl-5-oxide-1,2,5-oxadiazole -3-yl)-, 1,1-dioxide

To a mixture of 4-chloro-6-aminobenzene-1,3-disulfonamide (0.3 g, 1.05 mmol) and the product of Example 9a (0.23 g, 1.8 mmol) in dioxane (9 mL) was added concentrated HCl (1 mL). ) Was added dropwise. The reaction mixture was heated at 60 ° C. for 1 hour and then cooled to room temperature. The crude reaction mixture was separated by chromatography on silica gel and eluted with MeOH: CH ₂ Cl ₂ (0.5: 9.5 to 1: 9 to 1.5: 8.5) to give the title compound (0.24 g, 58% yield) as a white Obtained as a solid: mp 242-243 ° C. (decomposition);

Mass spectrum (API-TIS) m / z 394 (MH), 413 (MNH ₄ ⁺ ). _{C 10 H 10 ClN 5 O 6} S 2 calculated analytical values for: C, 30.34; H, 2.55 ; N, 17.69. Found: C, 30.25; H, 2.49; N, 17.42.

表題の化合物を実施例9bの手順に従うことにより、4-アミノ-6-トリフルオロメチルベンゼン-1,3-ジスルホンアミド(0.3 g, 0.94 mmol)、実施例9aの生成物(0.32 g, 2.5 mmol)および濃HCl (1 mL)から白色の固形物(0.16 g, 収率40%)として調製した。Mp 160℃。

質量スペクトル(API-TIS) m/z 428 (M-H)。C₁₁H₁₀F₃N₅O₆S₂に対し算出された分析値: C, 30.75; H, 2.34; N, 16.30; F, 13.33。実測値: C, 30.89; H, 2.33; N, 16.04; F, 13.27。 Example 10: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- (4-methyl-5-oxide-1,2,5-oxadiazole-3 -Yl) -6- (trifluoromethyl)-, 1,1-dioxide

By following the procedure of Example 9b for the title compound, 4-amino-6-trifluoromethylbenzene-1,3-disulfonamide (0.3 g, 0.94 mmol), the product of Example 9a (0.32 g, 2.5 mmol) ) And concentrated HCl (1 mL) as a white solid (0.16 g, 40% yield). Mp 160 ° C.

Mass spectrum (API-TIS) m / z 428 (MH). Analytical values calculated for C ₁₁ H ₁₀ F ₃ N ₅ O ₆ S ₂ : C, 30.75; H, 2.34; N, 16.30; F, 13.33. Found: C, 30.89; H, 2.33; N, 16.04; F, 13.27.

4-(6-クロロ-1,1-ジオキソ-7-スルファモイル-4H-ベンゾ[e]1,2,4-チアジアジン-3-イル)ブタン酸(2 mmol, 米国特許第3,287,360号中の手順に従って調製)をジメチルホルムアミド(3 mL)およびジクロロメタン(2 mL)の混合物に溶解した。別のフラスコ中で、(2R)-2,3-ビス(ニトロオキシ)プロピルアミン-硝酸塩(2 mmol、米国特許第2005/0059655 A1号、実施例12aに記載のように調製)をジクロロメタン(10 mL)中トリエチルアミン(0.25 mL)で処理して、(2R)-2,3-ビス(ニトロオキシ)プロピルアミンを生成させた。次いで、両方の溶液を一緒に混合し、室温で撹拌した。得られた混合物に、窒素雰囲気下で1-エチル-3-(3-ジメチルアミノプロピル)カルバミド塩酸塩(EDAC, 0.38 g, 2 mmol)およびジメチルアミノピリジン(DMAP, 0.24 g, 2 mmol)を加えた。次いで、得られた反応混合物を室温で一晩撹拌した。溶媒を真空下で蒸発させ、残留物を酢酸エチルで抽出し、水、塩水で洗浄し、硫酸ナトリウムで乾燥し、ろ過し、蒸発させた。生成物をシリカゲルのカラムクロマトグラフィーにより、5%メタノールのジクロロメタン液で溶出させて精製し、表題の化合物(0.38 g, 収率35%)を白色の固形物として得た: mp > 220℃;

質量スペクトル(API-TIS) m/z 545 (MH)⁺。 Example 11: 4H-1,2,4-benzothiadiazine-3-butanamide, 7- (aminosulfonyl) -N-[(2R) -2,3-bis (nitrooxy) propyl] -6-chloro- 1,1-dioxide

4- (6-Chloro-1,1-dioxo-7-sulfamoyl-4H-benzo [e] 1,2,4-thiadiazin-3-yl) butanoic acid (2 mmol, according to the procedure in US Pat. No. 3,287,360) Preparation) was dissolved in a mixture of dimethylformamide (3 mL) and dichloromethane (2 mL). In a separate flask, (2R) -2,3-bis (nitrooxy) propylamine-nitrate (2 mmol, prepared as described in US 2005/0059655 A1, Example 12a) was added dichloromethane (10 mL). ) With triethylamine (0.25 mL) to give (2R) -2,3-bis (nitrooxy) propylamine. Both solutions were then mixed together and stirred at room temperature. To the resulting mixture was added 1-ethyl-3- (3-dimethylaminopropyl) carbamide hydrochloride (EDAC, 0.38 g, 2 mmol) and dimethylaminopyridine (DMAP, 0.24 g, 2 mmol) under a nitrogen atmosphere. It was. The resulting reaction mixture was then stirred overnight at room temperature. The solvent was evaporated under vacuum and the residue was extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and evaporated. The product was purified by column chromatography on silica gel eluting with 5% methanol in dichloromethane to give the title compound (0.38 g, 35% yield) as a white solid: mp> 220 ° C .;

Mass spectrum (API-TIS) m / z 545 (MH) ⁺ .

4-アミノ-6-(トリフルオロメチル)ベンゼン-1,3-ジスルホンアミド(11.94 g, 37.4 mmol)および1-Boc-4-ピペリドン(8.19 g, 41.1 mmol, Fluka)のDMF (160 mL)溶液を、TLCにより示されるように最初の反応物質が消費されるまで、5〜7時間外界気圧下で加熱還流した。室温に冷却した後に、混合物を水に注ぎ入れ、EtOAcで抽出した。有機層をNaCl水溶液で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮して黄色の固形物を得た。クロマトグラフィー(シリカゲル, THF 1: 1 EtOAc:ヘキサン)によって、表題の化合物(16.95 g, 収率91%)を白色の固形物として得た。質量スペクトル(API-TIS) m/z 501.3 (MH⁺)、518.4 (MNH₄ ⁺)。 Example 12: Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[5- (nitrooxy) -1-oxopentyl] -6- (Trifluoromethyl)-, 1,1-dioxide
12a. Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -1'-carboxylic acid, 7- (aminosulfonyl) -6- (trifluoromethyl)-, 1,1-dimethylethyl ester, 1,1-dioxide

4-amino-6- (trifluoromethyl) benzene-1,3-disulfonamide (11.94 g, 37.4 mmol) and 1-Boc-4-piperidone (8.19 g, 41.1 mmol, Fluka) in DMF (160 mL) Was heated to reflux at ambient pressure for 5-7 hours until the first reactant was consumed as indicated by TLC. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with aqueous NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated to give a yellow solid. Chromatography (silica gel, THF 1: 1 EtOAc: hexanes) gave the title compound (16.95 g, 91% yield) as a white solid. Mass spectrum (API-TIS) m / z 501.3 (MH ⁺ ), 518.4 (MNH ₄ ⁺ ).

実施例12aの生成物(7.70 g, 15.4 mmol)の1,4-ジオキサン(50 mL)撹拌溶液に塩酸の1,4-ジオキサン液(4 M, 200 mL)を一度に加えると、濁った溶液が得られる。2時間後、反応混合物を元の容量の半分まで濃縮した。固形物をろ過により集め、ヘキサンで洗浄し、風乾し、真空乾燥して表題の化合物(5.10 g, 収率76%)を白色の固形物として得た: mp > 260℃。

質量スペクトル(API-TIS) m/z 401.2 (MH⁺)。 12b. Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6- (trifluoromethyl)-, 1,1-dioxide, monohydrochloride salt

To a stirred solution of the product of Example 12a (7.70 g, 15.4 mmol) in 1,4-dioxane (50 mL), a solution of hydrochloric acid in 1,4-dioxane (4 M, 200 mL) was added in one portion to give a cloudy solution. Is obtained. After 2 hours, the reaction mixture was concentrated to half of its original volume. The solid was collected by filtration, washed with hexane, air dried and vacuum dried to give the title compound (5.10 g, 76% yield) as a white solid: mp> 260 ° C.

Mass spectrum (API-TIS) m / z 401.2 (MH ⁺ ).

5-(ニトロオキシ)ペンタン酸(0.33 g, 2 mmol, Breschi, M. C. et al. J. Med. Chem. 2004, 47, 5597-5600により記載されているように調製)、N-(3-ジメチルアミノプロピル)-N'-エチルカルボジイミド塩酸塩(0.768 g, 4 mmol)、1-ヒドロキシベンゾトリアゾール水和物(0.541 g, 4 mmol)、および実施例12bの生成物(0.80 g, 1.8 mmol)のアセトニトリル(50 mL)撹拌混合物にトリエチルアミン(5 mL)を加えた。得られた混合物を室温で18時間撹拌し、濃縮し、EtOAcに溶解し、水、その後Na₂CO₃水溶液で洗浄した。有機層をMgSO₄で乾燥し、ろ過し、濃縮して固形物を得た。固形物をTHFに溶解し、クロマトグラフィー(シリカゲル, EtOAc)により精製して、表題の化合物(0.90 g, 収率92%)を白色の固形物として得た: mp 178℃ (分解);

質量スペクトル(API-TIS) m/z 546 (MH⁺)。 12c. Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[5- (nitrooxy) -1-oxopentyl] -6 -(Trifluoromethyl)-, 1,1-dioxide

5- (nitrooxy) pentanoic acid (0.33 g, 2 mmol, prepared as described by Breschi, MC et al. J. Med. Chem. 2004, 47, 5597-5600), N- (3-dimethylamino Propyl) -N'-ethylcarbodiimide hydrochloride (0.768 g, 4 mmol), 1-hydroxybenzotriazole hydrate (0.541 g, 4 mmol), and the product of Example 12b (0.80 g, 1.8 mmol) in acetonitrile (50 mL) Triethylamine (5 mL) was added to the stirred mixture. The resulting mixture was stirred at room temperature for 18 hours, concentrated, dissolved in EtOAc, washed with water followed by aqueous Na ₂ CO ₃ solution. The organic layer was dried over MgSO ₄ , filtered and concentrated to give a solid. The solid was dissolved in THF and purified by chromatography (silica gel, EtOAc) to give the title compound (0.90 g, 92% yield) as a white solid: mp 178 ° C. (decomposition);

Mass spectrum (API-TIS) m / z 546 (MH ⁺ ).

3-(6-クロロ-1,1-ジオキソ-7-スルファモイル-4H-ベンゾ[e]1,2,4-チアジアジン-3-イル)プロパン酸(0.74 g, 2.0 mmol, 米国特許第3,287,360号, 実施例2によって調製)および2-[2-(ニトロオキシ)エトキシ]エチルアミン、硝酸塩(0.46 g, 2.2 mmol, 国際公開公報第2005/030135 A2号の実施例11aに記載のように調製)のDMF (10 mL)およびジクロロメタン(10 mL)溶液にDMAP (49 mg, 0.4 mmol)およびEDAC (0.46 g, 2.4 mmol)を加えた。次いで、トリエチルアミン (0.31 mL, 0.22 g, 2.2 mmol)を滴下した。室温で2時間撹拌した後に、反応混合物を水とジクロロメタンとの間で分配した。水層をジクロロメタンで2回洗浄し、合わせた有機層を水、塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を真空下で除去し、粗生成物をシリカゲル、10%メタノール/ジクロロメタンでのカラムクロマトグラフィーにより精製した。粗固形物を酢酸エチル/ヘキサンから再結晶して、表題の化合物(0.35 g, 収率35%)を白色の固形物として得た: mp 175-178℃;

質量スペクトル(API-TIS) m/z 500 (MH⁺), 999 (2MH⁺)。 Example 13: 4H-1,2,4-benzothiadiazine-3-propanamide, 7- (aminosulfonyl) -6-chloro-N- [2- [2- (nitrooxy) ethoxy] ethyl]-, 1,1-dioxide

3- (6-Chloro-1,1-dioxo-7-sulfamoyl-4H-benzo [e] 1,2,4-thiadiazin-3-yl) propanoic acid (0.74 g, 2.0 mmol, U.S. Pat.No. 3,287,360, DMF (prepared according to example 2) and 2- [2- (nitrooxy) ethoxy] ethylamine, nitrate (0.46 g, 2.2 mmol, prepared as described in example 11a of WO 2005/030135 A2) To a solution of 10 mL) and dichloromethane (10 mL) were added DMAP (49 mg, 0.4 mmol) and EDAC (0.46 g, 2.4 mmol). Then, triethylamine (0.31 mL, 0.22 g, 2.2 mmol) was added dropwise. After stirring at room temperature for 2 hours, the reaction mixture was partitioned between water and dichloromethane. The aqueous layer was washed twice with dichloromethane, and the combined organic layers were washed with water and brine and dried over magnesium sulfate. The solvent was removed in vacuo and the crude product was purified by column chromatography on silica gel, 10% methanol / dichloromethane. The crude solid was recrystallized from ethyl acetate / hexanes to give the title compound (0.35 g, 35% yield) as a white solid: mp 175-178 ° C .;

Mass spectrum (API-TIS) m / z 500 (MH ⁺ ), 999 (2MH ⁺ ).

表題の化合物を実施例11の手順に従うことにより、2-(ニトロオキシ)エチルアミン-硝酸塩(2 mmol) (米国特許第2004/0024057号, 実施例22aに記載のように調製)および4-(6-クロロ-1,1-ジオキソ-7-スルファモイル-4H-ベンゾ[e]1,2,4-チアジアジン-3-イル)ブタン酸(2 mmol)の反応によって調製した。生成物をシリカゲルのカラムクロマトグラフィーにより、5%メタノールのジクロロメタン液で溶出させて精製し、表題の化合物(0.29 g, 収率31%)を白色の固形物として得た: mp 168-170℃;

質量スペクトル(API-TIS) m/z 470 (MH)⁺、472 (MH + 2)⁺。 Example 14: 4H-1,2,4-benzothiadiazine-3-butanamide, 7- (aminosulfonyl) -6-chloro-N- [2- (nitrooxy) ethyl]-, 1,1-dioxide

The title compound was prepared according to the procedure of Example 11 to give 2- (nitrooxy) ethylamine-nitrate (2 mmol) (prepared as described in US 2004/0024057, Example 22a) and 4- (6- Prepared by reaction of chloro-1,1-dioxo-7-sulfamoyl-4H-benzo [e] 1,2,4-thiadiazin-3-yl) butanoic acid (2 mmol). The product was purified by column chromatography on silica gel eluting with 5% methanol in dichloromethane to give the title compound (0.29 g, 31% yield) as a white solid: mp 168-170 ° C .;

Mass spectrum (API-TIS) m / z 470 (MH) ⁺ , 472 (MH + 2) ⁺ .

塩化オキサリル(0.3 mL, 3.4 mmol)を3-[(ニトロオキシ)メチル]安息香酸(米国特許第2004/0024057号, 実施例43aに記載のように調製, 0.53 g, 2.7 mmol)のCH₂Cl₂ (50 mL)およびDMF (50 μL)溶液に加え、室温で1.5時間撹拌した。反応混合物を蒸発乾固し、真空下で乾燥して、表題の化合物を白色の固形物として得た。生成物をさらには精製せずに次の段階で用いた。

Example 15: Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[3-[(nitrooxy) methyl] benzoyl]- 6- (Trifluoromethyl)-, 1,1-dioxide
15a. Benzoyl chloride, 3-[(nitrooxy) methyl]-

Oxalyl chloride (0.3 mL, 3.4 mmol) was added to 3-[(nitrooxy) methyl] benzoic acid (prepared as described in US Patent No. 2004/0024057, Example 43a, 0.53 g, 2.7 mmol) of CH ₂ Cl ₂ (50 mL) and DMF (50 μL) solution, and stirred at room temperature for 1.5 hours. The reaction mixture was evaporated to dryness and dried under vacuum to give the title compound as a white solid. The product was used in the next step without further purification.

実施例15aの生成物(2.58 mmol)、および実施例12bの生成物(1.13 g, 2.58 mmol)のDMF (20 mL)撹拌混合物にトリエチルアミン(5 mL)を滴下した。1時間後、混合物をEtOAcで希釈し、NaHCO₃水溶液で2回洗浄した。有機層をNa₂SO₄で乾燥し、ろ過し、濃縮した。残留物のクロマトグラフィー(シリカゲル, 1:5のTHF:EtOAc)により、表題の化合物(1.21 g, 収率81%)を白色の固形物として得た。

質量スペクトル(API-TIS) m/z 580 (MH⁺)。 15b. Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[3-[(nitrooxy) methyl] benzoyl] -6- (Trifluoromethyl)-, 1,1-dioxide

Triethylamine (5 mL) was added dropwise to a stirred mixture of the product of Example 15a (2.58 mmol) and the product of Example 12b (1.13 g, 2.58 mmol) in DMF (20 mL). After 1 hour, the mixture was diluted with EtOAc and washed twice with aqueous NaHCO ₃ solution. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Chromatography of the residue (silica gel, 1: 5 THF: EtOAc) gave the title compound (1.21 g, 81% yield) as a white solid.

Mass spectrum (API-TIS) m / z 580 (MH ⁺ ).

発煙硝酸(90%; 6 mL, 143 mmol)を氷冷無水酢酸(30 mL)に加え、氷浴中で10分間撹拌した。次いで、2,2-ビス(ヒドロキシメチル)- プロピオン酸 (Aldrich, 2.59 g, 19.3 mmol)の酢酸エチル(30 mL)液を加え、得られた混合物を室温で20分間撹拌し、次に45℃にて真空下で蒸発乾固した。残留物を3 N HCl (100 mL)と酢酸エチル(100 mL)との間で分配した。有機抽出液を水、NaClで洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮し、真空下で乾燥した。粗材料をエチルエーテル(3 mL)に溶解し、ヘキサン(100 mL)で摩砕した。固形物を回収し、真空下で乾燥して、表題の化合物を白色の固形物(2.89 g, 収率67%)として得た: mp 66-69℃;

質量スペクトル(API-TIS) m/z 223 (M-H)。 Example 16. Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[2-methyl-3- (nitrooxy) -2 -[(Nitrooxy) methyl] -1-oxopropyl] -6- (trifluoromethyl)-, 1,1-dioxide
16a. Propanoic acid, 2-methyl-3- (nitrooxy) -2-[(nitrooxy) methyl]-

Fuming nitric acid (90%; 6 mL, 143 mmol) was added to ice-cold acetic anhydride (30 mL) and stirred in an ice bath for 10 minutes. Then 2,2-bis (hydroxymethyl) -propionic acid (Aldrich, 2.59 g, 19.3 mmol) in ethyl acetate (30 mL) was added and the resulting mixture was stirred at room temperature for 20 minutes, then at 45 ° C. And evaporated to dryness under vacuum. The residue was partitioned between 3 N HCl (100 mL) and ethyl acetate (100 mL). The organic extract was washed with water, NaCl, dried over Na ₂ SO ₄ , filtered, concentrated and dried under vacuum. The crude material was dissolved in ethyl ether (3 mL) and triturated with hexane (100 mL). The solid was collected and dried under vacuum to give the title compound as a white solid (2.89 g, 67% yield): mp 66-69 ° C .;

Mass spectrum (API-TIS) m / z 223 (MH).

塩化オキサリル(150 μL, 1.7 mmol)を実施例16aの生成物(0.32 g, 1.4 mmol)のCH₂Cl₂ (10 mL)およびDMF (10 μL)溶液に加え、室温で2.5時間撹拌した。反応混合物を蒸発乾固し、真空下で乾燥して、表題の化合物を淡色の油状物として得た。生成物をさらには精製せずに次の段階で用いた。

16b. Propanoyl chloride, 2-methyl-3- (nitrooxy) -2-[(nitrooxy) methyl]-

Oxalyl chloride (150 μL, 1.7 mmol) was added to a solution of the product of Example 16a (0.32 g, 1.4 mmol) in CH ₂ Cl ₂ (10 mL) and DMF (10 μL) and stirred at room temperature for 2.5 hours. The reaction mixture was evaporated to dryness and dried under vacuum to give the title compound as a pale oil. The product was used in the next step without further purification.

トリエチルアミン(0.36 mL, 2.6 mmol)を実施例16bの粗生成物および実施例12bの生成物(0.57 g, 1.3 mmol)のアセトニトリル(20 mL)混合物に加え、室温で一晩撹拌した。反応混合物を減圧下で蒸発乾固した。残留物を3 N HCl (10 mL)と酢酸エチル(150 mL)との間で分配した。有機抽出液を水、塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮し、真空下で乾燥した。粗生成物を酢酸エチル(3 mL)に溶解し、CHCl₃ (50 mL)で摩砕した。固形物を回収し、真空下で乾燥して、表題の化合物を白色の固形物(0.59 g, 収率75%)として得た: mp >140℃ (分解);

質量スペクトル(API-TIS) m/z 607 (MH⁺)。C₁₇H₂₁F₃N₆O₁₁S₂に対し算出された分析値: C, 33.67; H, 3.49; N, 13.86; 実測値: C, 33.42; H, 3.32; N, 13.60。 16c. Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[2-methyl-3- (nitrooxy) -2- [ (Nitrooxy) methyl] -1-oxopropyl] -6- (trifluoromethyl)-, 1,1-dioxide

Triethylamine (0.36 mL, 2.6 mmol) was added to a mixture of the crude product of Example 16b and the product of Example 12b (0.57 g, 1.3 mmol) in acetonitrile (20 mL) and stirred at room temperature overnight. The reaction mixture was evaporated to dryness under reduced pressure. The residue was partitioned between 3 N HCl (10 mL) and ethyl acetate (150 mL). The organic extract was washed with water, brine, dried over Na ₂ SO ₄ , filtered, concentrated and dried under vacuum. The crude product was dissolved in ethyl acetate (3 mL) and triturated with CHCl ₃ (50 mL). The solid was collected and dried under vacuum to give the title compound as a white solid (0.59 g, 75% yield): mp> 140 ° C. (decomposition);

Mass spectrum (API-TIS) m / z 607 (MH ⁺ ). Calculated for C ₁₇ H ₂₁ F ₃ N ₆ O ₁₁ S ₂ : C, 33.67; H, 3.49; N, 13.86; Found: C, 33.42; H, 3.32; N, 13.60.

5-(ニトロオキシ)ペンタン-1-オール(50 mmol) (国際公開公報第2004/012659号, 実施例3bに記載のように調製)を実施例1bの手順に従いDess-Martinペルヨージナンにより酸化して、表題の化合物を得た。得られた粗生成物をさらには精製せずに次の段階でそのまま用いた。

Example 17: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide
17a. Pentanal, 5- (Nitrooxy)-

5- (Nitrooxy) pentan-1-ol (50 mmol) (prepared as described in WO 2004/012659, Example 3b) was oxidized with Dess-Martin periodinane according to the procedure of Example 1b, The title compound was obtained. The resulting crude product was used directly in the next step without further purification.

表題の化合物を実施例1cの手順に従い実施例17aの生成物および2-アミノ-6-クロロ-1,3-ベンゼンジスルホンアミド (14.35 g, 50 mmol)の反応により調製した。生成物をシリカゲルのカラムクロマトグラフィーにより4%メタノールのジクロロメタン液で溶出させて精製し、表題の化合物(8.1 g, 収率39%)を白色の固形物として得た: mp 171-179℃;

質量スペクトル(API-TIS) m/z 432 (MNH₄)⁺。 17b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide

The title compound was prepared by reaction of the product of Example 17a and 2-amino-6-chloro-1,3-benzenedisulfonamide (14.35 g, 50 mmol) following the procedure of Example 1c. The product was purified by column chromatography on silica gel eluting with 4% methanol in dichloromethane to give the title compound (8.1 g, 39% yield) as a white solid: mp 171-179 ° C .;

Mass spectrum (API-TIS) m / z 432 (MNH ₄ ) ⁺ .

実施例17bの生成物をCHIRACEL OJ-Hカラムでの超臨界流体キラルクロマトグラフィーにより、280 nMのUV検出で液体CO₂:メタノール(70:30)を用いて鏡像異性体に分離した。各異性体の純度を分析キラルカラムOJ-H (150×4.6 mm)により、1 mL/分の流速でメタノール:水(60:40)の等張溶媒系を用いて測定した。鏡像異性体1および2の保持時間は、それぞれ12.26および14.76分であった。 17c. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide, (3R )-(Enantiomer 1) and 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) butyl]-, 1 , 1-Dioxide, (3S)-(Enantiomer 2)

The product of Example 17b was separated into enantiomers by supercritical fluid chiral chromatography on a CHIRACEL OJ-H column using liquid CO ₂ : methanol (70:30) with 280 nM UV detection. The purity of each isomer was measured by analytical chiral column OJ-H (150 × 4.6 mm) using a methanol: water (60:40) isotonic solvent system at a flow rate of 1 mL / min. Retention times for enantiomers 1 and 2 were 12.26 and 14.76 minutes, respectively.

4-アミノ-6-クロロ-1,3-ベンゼンジスルホンアミド(Aldrich, Wisconsin; 40.7 g, 0.142 mol)、4-ピペリドン一水和物塩酸塩(Aldrich, Wisconsin; 24.1 g, 0.16 mol)、N,N-ジメチルアセトアミド(120 mL)、トルエン(600 mL)およびp-トルエンスルホン酸一水和物(Aldrich, Wisconsin; 1.0 g, 5.26 mmol, 0.04当量)の混合物を、水が蒸留し終わるまで、3〜4時間加熱還流した(180〜200℃)。反応混合物を周囲温度に冷却し、固形物をろ過により除去し、その後トルエンで洗浄して粗生成物(70 g)を得た。粗生成物を乳棒と乳鉢ですりつぶし、次いで熱水(70℃)から再結晶した。固形物をろ過により除去し、水(50 mL)で洗浄して、表題の化合物(43.9 g, 収率76.4%)を白色の固形物として得た: mp 265℃ (分解);

質量スペクトル(API-TIS) m/z 367 (MH⁺)。 Example 18: Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6-chloro-1 '-[5- (nitrooxy) -1 -Oxopentyl]-, 1,1-dioxide
18a. Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6-chloro-, 1,1-dioxide, monohydrochloride

4-amino-6-chloro-1,3-benzenedisulfonamide (Aldrich, Wisconsin; 40.7 g, 0.142 mol), 4-piperidone monohydrate hydrochloride (Aldrich, Wisconsin; 24.1 g, 0.16 mol), N, Add a mixture of N-dimethylacetamide (120 mL), toluene (600 mL) and p-toluenesulfonic acid monohydrate (Aldrich, Wisconsin; 1.0 g, 5.26 mmol, 0.04 equiv.) Until 3 Heated to reflux (180-200 ° C.) for ˜4 hours. The reaction mixture was cooled to ambient temperature and the solid was removed by filtration and then washed with toluene to give the crude product (70 g). The crude product was ground with a pestle and mortar and then recrystallized from hot water (70 ° C.). The solid was removed by filtration and washed with water (50 mL) to give the title compound (43.9 g, 76.4% yield) as a white solid: mp 265 ° C. (decomposition);

Mass spectrum (API-TIS) m / z 367 (MH ⁺ ).

5-(ニトロオキシ)ペンタン酸(5.35 g, 32.8 mmol, Breschi, M. C. et al, J. Med. Chem. 47, 5597-5600, 2004により記載されているように調製)、N-(3-ジメチルアミノプロピル)-N'-エチルカルボジイミド塩酸塩(6.29 g, 32.8 mmol)、1-ヒドロキシベンゾトリアゾール水和物(4.44 g, 32.8 mmol)、および実施例18aの生成物(8.82 g, 21.9 mmol)のアセトニトリル(180 mL)撹拌混合物に、トリエチルアミン(15.3 mL, 110 mmol)を加えた。得られた混合物を室温で5時間撹拌し、濃縮して揮発性物質を除去し、EtOAcで処理し、水、NaHCO₃水溶液、およびNaCl水溶液で洗浄した。有機層をNa₂SO₄で乾燥し、ろ過し、濃縮して固形物を得た。粗生成物のクロマトグラフィー(シリカゲル、負荷の場合THF、溶出の場合EtOAc)により、表題の化合物(698 mg, 収率6.2%)を白色の固形物として得た: mp 155℃ (分解);

質量スペクトル(API-TIS) m/z 512および514 (それぞれ³⁵Clおよび³⁷ClのMH⁺)。 18b. Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6-chloro-1 '-[5- (nitrooxy) -1-oxo Pentyl]-, 1,1-dioxide

5- (Nitrooxy) pentanoic acid (5.35 g, 32.8 mmol, prepared as described by Breschi, MC et al, J. Med. Chem. 47, 5597-5600, 2004), N- (3-dimethylamino Propyl) -N'-ethylcarbodiimide hydrochloride (6.29 g, 32.8 mmol), 1-hydroxybenzotriazole hydrate (4.44 g, 32.8 mmol), and the product of Example 18a (8.82 g, 21.9 mmol) in acetonitrile (180 mL) To the stirred mixture was added triethylamine (15.3 mL, 110 mmol). The resulting mixture was stirred at room temperature for 5 h, concentrated to remove volatiles, treated with EtOAc, washed with water, aqueous NaHCO ₃ , and aqueous NaCl. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give a solid. Chromatography of the crude product (silica gel, THF for loading, EtOAc for elution) gave the title compound (698 mg, 6.2% yield) as a white solid: mp 155 ° C. (decomposition);

Mass spectrum (API-TIS) m / z 512 and 514 ( ³⁵ Cl and ³⁷ Cl MH ^+, respectively).

2,2-ジメチル-3-(ニトロオキシ)プロパン酸(1.11 g, 6.82 mmol, 米国特許第5,428,061号, 実施例3に記載のように調製)の塩化メチレン(15 mL)液に、塩化オキサリル(1.0 mL, 11.5 mmol)およびDMF (50 μL)を加えた。反応混合物を室温で30分間撹拌し、濃縮乾固し、40分間真空で乾燥して表題の化合物(1.28 g, 収率100%)を得た。

Example 19: Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[2,2-dimethyl-3- (nitrooxy) -1-oxopropyl] -6- (trifluoromethyl)-, 1,1-dioxide
19a. Propanoyl chloride, 2,2-dimethyl-3- (nitrooxy)-

To a solution of 2,2-dimethyl-3- (nitrooxy) propanoic acid (1.11 g, 6.82 mmol, U.S. Pat.No. 5,428,061, prepared as described in Example 3) in methylene chloride (15 mL) was added oxalyl chloride (1.0 mL). mL, 11.5 mmol) and DMF (50 μL) were added. The reaction mixture was stirred at room temperature for 30 minutes, concentrated to dryness and dried in vacuo for 40 minutes to give the title compound (1.28 g, 100% yield).

実施例12bの生成物(176.3 mg, 0.40 mmol)のDMF (1 mL)液を実施例19aの生成物(120.4 mg, 0.643 mmol)、その後トリエチルアミン (0.5 mL, 3.6 mmol)に加えた。反応混合物を室温で1時間撹拌し、真空下で濃縮乾固した。粗生成物をシリカゲルのクロマトグラフィーにより分離しメタノール:ジクロロメタン(0:100、次いで2:98、次いで5:95)で溶出させて、表題の化合物(135.2 mg, 収率61%)を得た: mp 152-156℃ (分解);

質量スペクトル(API-TIS) m/z 546 (MH⁺)、563 (MNH₄ ⁺)、568 (MNa⁺)。 19b. Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[2,2-dimethyl-3- (nitrooxy) -1 -Oxopropyl] -6- (trifluoromethyl)-, 1,1-dioxide

A solution of the product of Example 12b (176.3 mg, 0.40 mmol) in DMF (1 mL) was added to the product of Example 19a (120.4 mg, 0.643 mmol) followed by triethylamine (0.5 mL, 3.6 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated to dryness under vacuum. The crude product was separated by chromatography on silica gel and eluted with methanol: dichloromethane (0: 100 then 2:98 then 5:95) to give the title compound (135.2 mg, 61% yield): mp 152-156 ° C (decomposition);

Mass spectrum (API-TIS) m / z 546 (MH ⁺ ), 563 (MNH ₄ ⁺ ), 568 (MNa ⁺ ).

塩化オキサリル(1.9 mL, 2.69 g, 21.2 mmol)を0℃で実施例5aの生成物(2.5 g, 14.1 mmol)のCH₂Cl₂ (7 mL)溶液に滴下した。この溶液に、DMF (35 μL)を滴下した。反応混合物を0℃で10分間、次に室温で30分間撹拌した。溶媒の蒸発後、残留物を真空下で乾燥して、表題の化合物を半固形物として得た。生成物をさらには精製せずにすぐに用いた。

質量スペクトル(API-TIS) m/z 212 (MNH₄ ⁺)。 Example 20: 4H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3- [5- (nitrooxy) pentyl]-, 1,1-dioxide
20a. Hexanoyl chloride, 6- (nitrooxy)-

Oxalyl chloride (1.9 mL, 2.69 g, 21.2 mmol) was added dropwise at 0 ° C. to a solution of the product of Example 5a (2.5 g, 14.1 mmol) in CH ₂ Cl ₂ (7 mL). To this solution, DMF (35 μL) was added dropwise. The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 30 minutes. After evaporation of the solvent, the residue was dried under vacuum to give the title compound as a semi-solid. The product was used immediately without further purification.

Mass spectrum (API-TIS) m / z 212 (MNH ₄ ⁺ ).

4-クロロ-6-アミノベンゼン-1,3-ジスルホンアミド(3.22 g, 11.3 mmol)および実施例20aの生成物(14.1 mmol)のジオキサン(30 mL)混合物を110℃で30分間還流した。反応混合物を室温に冷却した。溶媒の蒸発後、残留物をEtOAcで洗浄し、真空下で乾燥して、表題の化合物(2.3 g, 収率46%)を白色の固形物として得た: mp 180-182℃。

質量スペクトル(API-TIS) m/z 443 (M-H)、445 (MH⁺)、462 (MNa⁺)。C₁₂H₁₇ClN₄O₈S₂に対し算出された分析値: C, 32.40; H, 3.85; N, 12.59。実測値: C, 32.32; H, 3.69: N, 12.42。 20b. Hexanamide, N- [2,4-bis (aminosulfonyl) -5-chlorophenyl] -6- (nitrooxy)-

A mixture of 4-chloro-6-aminobenzene-1,3-disulfonamide (3.22 g, 11.3 mmol) and the product of Example 20a (14.1 mmol) in dioxane (30 mL) was refluxed at 110 ° C. for 30 minutes. The reaction mixture was cooled to room temperature. After evaporation of the solvent, the residue was washed with EtOAc and dried under vacuum to give the title compound (2.3 g, 46% yield) as a white solid: mp 180-182 ° C.

Mass spectrum (API-TIS) m / z 443 (MH), 445 (MH ⁺ ), 462 (MNa ⁺ ). Analytical value calculated for C ₁₂ H ₁₇ ClN ₄ O ₈ S ₂ : C, 32.40; H, 3.85; N, 12.59. Found: C, 32.32; H, 3.69: N, 12.42.

実施例20bの生成物(1.3 g, 2.9 mmol)の水(15 mL)懸濁液に、0℃でNaOH (0.45 g, 11.2 mmol)の水溶液(w/w)を滴下した。反応混合物を0℃で15分間、次に室温で3時間撹拌した。清澄な溶液を0℃に冷却し、1 N HClで酸性化した。白色の沈殿物をろ過し、水で洗浄し、真空下で乾燥して、表題の化合物(0.7 g, 収率56%)を白色の固形物として得た: mp 170-172℃。

質量スペクトル(API-TIS) m/z 425 (M-H)、427 (MH⁺)、444 (MNH₄ ⁺)。C₁₂H₁₅ClN₄O₇S₂に対し算出された分析値: C, 33.77; H, 3.54; N, 13.13; S, 15.02; Cl, 8.31。実測値: C, 33.55; H, 3.28; N, 12.93; S, 14.83; Cl, 8.46。 20c. 4H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3- [5- (nitrooxy) pentyl]-, 1,1-dioxide

An aqueous solution (w / w) of NaOH (0.45 g, 11.2 mmol) was added dropwise at 0 ° C. to a suspension of the product of Example 20b (1.3 g, 2.9 mmol) in water (15 mL). The reaction mixture was stirred at 0 ° C. for 15 minutes and then at room temperature for 3 hours. The clear solution was cooled to 0 ° C. and acidified with 1 N HCl. The white precipitate was filtered, washed with water and dried under vacuum to give the title compound (0.7 g, 56% yield) as a white solid: mp 170-172 ° C.

Mass spectrum (API-TIS) m / z 425 (MH), 427 (MH ⁺ ), 444 (MNH ₄ ⁺ ). Calculated values for C ₁₂ H ₁₅ ClN ₄ O ₇ S ₂ : C, 33.77; H, 3.54; N, 13.13; S, 15.02; Cl, 8.31. Found: C, 33.55; H, 3.28; N, 12.93; S, 14.83; Cl, 8.46.

(S)(-)-3-アミノ-1,2-プロパンジオール(5.0 g, 54.9 mmol, HD 382, 実施例12aに記載のように調製)に、発煙硝酸(2.75 mL)および硝酸化試薬(無水酢酸41.5 mLおよび発煙硝酸11.6 mL)を加えて、定量的な収率の表題の化合物(薄緑色の固形物)を得た:

質量スペクトル(API-TIS) m/z 182 (MH-HNO₃)⁺。 Example 21: 4H-1,2,4-benzothiadiazine-3-butanamide, 7- (aminosulfonyl) -N-[(2S) -2,3-bis (nitrooxy) propyl] -6-chloro- 1,1-dioxide
21a. 1,2-propanediol, 3-amino-, dinitrate (ester), (2S)-, nitrate (1: 1) (salt)

(S) (-)-3-Amino-1,2-propanediol (5.0 g, 54.9 mmol, HD 382, prepared as described in Example 12a) was combined with fuming nitric acid (2.75 mL) and nitrating reagent ( Acetic anhydride (41.5 mL and fuming nitric acid 11.6 mL) was added to give a quantitative yield of the title compound (light green solid):

Mass spectrum (API-TIS) m / z 182 (MH-HNO ₃ ) ⁺ .

4-(6-クロロ-1,1-ジオキソ-7-スルファモイル-4H-ベンゾ[e]1,2,4-チアジアジン-3-イル)ブタン酸(3 mmol, 米国特許第3,287,360号に記載のように調製)を無水DMF (3 mL)に溶解した。別のフラスコ中で、実施例21aの生成物(0.73 g, 3 mmol)を無水CH₂Cl₂ (10 mL)中トリエチルアミン(0.42 mL)で処理して、(2S)-2,3-ビス(ニトロオキシ)プロピルアミンを生成させた。両方の溶液を合わせ、引き続いて1-エチル-3-(3-ジメチルアミノプロピル)カルバミド塩酸塩(EDAC) (0.58 g, 3 mmol)およびジメチルアミノピリジン(DMAP) (0.37 g, 3 mmol)の添加を行った。得られた混合物を窒素下、室温で一晩撹拌した。溶媒を高真空下で蒸発させ、残留物をシリカゲルフラッシュカラムクロマトグラフィーにより5% MeOHのCH₂Cl₂液で溶出させて精製し、表題の化合物(0.85 g, 収率52%)を白色の固形物として得た: mp 140℃ (分解);

質量スペクトル(API-TIS) m/z 545 (MH)⁺、562 (MNH₄)⁺。 21b. 4H-1,2,4-Benzothiadiazine-3-butanamide, 7- (aminosulfonyl) -N-[(2S) -2,3-bis (nitrooxy) propyl] -6-chloro-, 1 , 1-dioxide

4- (6-Chloro-1,1-dioxo-7-sulfamoyl-4H-benzo [e] 1,2,4-thiadiazin-3-yl) butanoic acid (3 mmol, as described in U.S. Pat.No. 3,287,360) Was dissolved in anhydrous DMF (3 mL). In a separate flask, the product of Example 21a (0.73 g, 3 mmol) was treated with triethylamine (0.42 mL) in anhydrous CH ₂ Cl ₂ (10 mL) to give (2S) -2,3-bis ( Nitrooxy) propylamine was produced. Both solutions were combined, followed by addition of 1-ethyl-3- (3-dimethylaminopropyl) carbamide hydrochloride (EDAC) (0.58 g, 3 mmol) and dimethylaminopyridine (DMAP) (0.37 g, 3 mmol) Went. The resulting mixture was stirred overnight at room temperature under nitrogen. The solvent was evaporated under high vacuum and the residue was purified by silica gel flash column chromatography eluting with 5% MeOH in CH ₂ Cl ₂ to give the title compound (0.85 g, 52% yield) as a white solid Obtained as: mp 140 ℃ (decomposition);

Mass spectrum (API-TIS) m / z 545 (MH) ⁺ , 562 (MNH ₄ ) ⁺ .

4,5-ビス(ニトロオキシ)ペンタン-1-オール(1.21 g, 5.76 mmol, 国際公開公報第2005/030135 A2号, 実施例27dに記載のように調製)のアセトン20 mL溶液に、撹拌しながら、Jones試薬(1 M, 12 mL, 12 mmol, Fieser, L. F. and Fieser, M.「Reagents for Organic Synthesis」Vol. 1, p.142, 1967に記載のように調製)を滴下した。青緑色の沈殿物がすぐに生じた。橙色が消えずに残った後、反応混合物をさらに30分間撹拌した。過剰なJones試薬をイソプロピルアルコール、引き続きヒドロ亜硫酸ナトリウムで分解させた。反応混合物を、セライトを通してろ過し、ろ液を真空下で蒸発させた。残留物をエーテルに溶解し、水、塩水で洗浄し、硫酸マグネシウムで乾燥した。真空下での溶媒の除去により、表題の化合物(1.28 g, 5.74 mmol, 収率98%)を無色の油状物として得た:

質量スペクトル(API-TIS) m/z 447 (2M-H⁺)。 Example 22: Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[4,5-bis (nitrooxy) -1- Oxopentyl] -6-chloro-, 1,1-dioxide
22a. Pentanoic acid, 4,5-bis (nitrooxy)-

To a stirred solution of 4,5-bis (nitrooxy) pentan-1-ol (1.21 g, 5.76 mmol, International Publication No. 2005/030135 A2, prepared as described in Example 27d) in 20 mL of acetone, with stirring Jones reagent (1 M, 12 mL, 12 mmol, Fieser, LF and Fieser, M. Prepared as described in “Reagents for Organic Synthesis” Vol. 1, p. 142, 1967) was added dropwise. A blue-green precipitate formed immediately. After the orange color remained intact, the reaction mixture was stirred for an additional 30 minutes. Excess Jones reagent was destroyed with isopropyl alcohol followed by sodium hydrosulfite. The reaction mixture was filtered through celite and the filtrate was evaporated under vacuum. The residue was dissolved in ether, washed with water and brine, and dried over magnesium sulfate. Removal of the solvent under vacuum gave the title compound (1.28 g, 5.74 mmol, 98% yield) as a colorless oil:

Mass spectrum (API-TIS) m / z 447 (2M-H ⁺ ).

実施例18aの生成物(1.01 g, 2.5 mmol)および実施例22aの生成物(0.83 g, 3.7 mmol)のDMF 20 mL溶液にDMAP (0.06 g, 0.5 mmol)およびEDAC (0.709 g, 3.7 mmol)を加えた。次いで、トリエチルアミン(1.04 mL, 7.5 mmol)を滴下した。室温で一晩撹拌した後に、溶媒を真空下で除去した。残留物を酢酸エチル/メタノールに再溶解し、水と酢酸エチルとの間で分配した。有機層を水、塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を真空下で除去し、粗生成物をシリカゲル、5%メタノール/酢酸エチルでのカラムクロマトグラフィーによって精製した。溶媒の蒸発により、表題の化合物(0.53 g, 0.93 mmol, 収率37%)を白色の無定形固体として得た:

質量スペクトル(API-TIS) m/z 573 (MH⁺)、590 (MNH₄ ⁺)、1147 (2MH⁺)。 22b. Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[4,5-bis (nitrooxy) -1-oxopentyl ] -6-Chloro-, 1,1-dioxide

DMAP (0.06 g, 0.5 mmol) and EDAC (0.709 g, 3.7 mmol) in a 20 mL DMF solution of the product of Example 18a (1.01 g, 2.5 mmol) and the product of Example 22a (0.83 g, 3.7 mmol) Was added. Then triethylamine (1.04 mL, 7.5 mmol) was added dropwise. After stirring at room temperature overnight, the solvent was removed under vacuum. The residue was redissolved in ethyl acetate / methanol and partitioned between water and ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. The solvent was removed in vacuo and the crude product was purified by column chromatography on silica gel, 5% methanol / ethyl acetate. Evaporation of the solvent gave the title compound (0.53 g, 0.93 mmol, 37% yield) as a white amorphous solid:

Mass spectrum (API-TIS) m / z 573 (MH ⁺ ), 590 (MNH ₄ ⁺ ), 1147 (2MH ⁺ ).

トリエチルアミン(0.70 mL, 5.0 mmol)を実施例16bの粗生成物および実施例18aの生成物(1.03 g, 2.5 mmol)のアセトニトリル(30 mL)混合物に加え、室温で一晩撹拌した。反応混合物を減圧下で蒸発乾固した。残留物を3 N HCl (10 mL)と酢酸エチル(150 mL)との間で分配した。有機抽出液を水、塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮し、真空下で乾燥した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(1:1〜3:1の勾配、2:1でR_f=0.13)で溶出させて分離し、表題の化合物を白色の固形物(0.31 g, 収率22%)として得た: mp 142-145℃;

質量スペクトル(API-TIS) m/z 573 (MH⁺)。 Example 23: Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6-chloro-1 '-[2-methyl-3- ( Nitrooxy) -2-[(nitrooxy) methyl] -1-oxopropyl]-, 1,1-dioxide

Triethylamine (0.70 mL, 5.0 mmol) was added to a mixture of the crude product of Example 16b and the product of Example 18a (1.03 g, 2.5 mmol) in acetonitrile (30 mL) and stirred at room temperature overnight. The reaction mixture was evaporated to dryness under reduced pressure. The residue was partitioned between 3 N HCl (10 mL) and ethyl acetate (150 mL). The organic extract was washed with water, brine, dried over Na ₂ SO ₄ , filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with EtOAc / hexane (1: 1 to 3: 1 gradient, 2: 1 with R _f = 0.13) to give the title compound as a white solid (0.31 g, Yield 22%): mp 142-145 ° C;

Mass spectrum (API-TIS) m / z 573 (MH ⁺ ).

6-ヒドロキシヘキサン酸エチル(3.25 mL, 20 mmol)の無水CH₂Cl₂ (400 mL)およびアルミナ(30 g)懸濁液に、クロロクロム酸ピリジニウム(21.56 g, 100 mmol)を加え、反応混合物を窒素下で20分間激しく撹拌した。ろ過後、溶液を、シリカゲルを通しろ過して不純物を除去した。溶媒を減圧下で部分的に除去し、粗生成物をさらには精製せずに用いた。 Example 24: 6-chloro-3- (5-hydroxypentyl) -3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide
24a. Hexanoic acid, 6-oxo-, ethyl ester

To a suspension of ethyl 6-hydroxyhexanoate (3.25 mL, 20 mmol) in anhydrous CH ₂ Cl ₂ (400 mL) and alumina (30 g) was added pyridinium chlorochromate (21.56 g, 100 mmol) and the reaction mixture Was stirred vigorously under nitrogen for 20 minutes. After filtration, the solution was filtered through silica gel to remove impurities. The solvent was partially removed under reduced pressure and the crude product was used without further purification.

表題の化合物を実施例1cの手順に従って、実施例24aの生成物および4-アミノ-6-クロロ-1,3-ベンゼンジスルホンアミドの反応により調製した。表題の化合物を白色の固形物(2.51 g, 収率59%)として得た: mp 90℃;

質量スペクトル(API-TIS) m/z 426 (MH)⁺、443 (MNH₄)⁺。 24b. 2H-1,2,4-Benzothiadiazine-3-pentanoic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, ethyl ester, 1,1-dioxide

The title compound was prepared by reaction of the product of Example 24a and 4-amino-6-chloro-1,3-benzenedisulfonamide according to the procedure of Example 1c. The title compound was obtained as a white solid (2.51 g, 59% yield): mp 90 ° C .;

Mass spectrum (API-TIS) m / z 426 (MH) ⁺ , 443 (MNH ₄ ) ⁺ .

実施例24bの生成物(0.43 g, 1.0 mmol)の無水THF (5 mL)溶液に、0.5 M AlH₃溶液(5 mL, 2.5 mmol)を加え、反応混合物を窒素下、室温で30分間撹拌した。反応混合物をNH₄Cl飽和水溶液でクエンチングし、次いで酸性化した。減圧下での溶媒の除去後、残留物をEtOAcと水との間で分配し、水層をEtOAcで(2×)さらに抽出した。合わせた有機層を塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、溶媒を減圧下で除去した。得られた残留物をシリカゲルフラッシュカラムクロマトグラフィーにより8% MeOHのCH₂Cl₂液で溶出させて精製し、表題の化合物(0.37 g, 収率95%)を白色の固形物として得た: mp 190℃;

質量スペクトル(API-TIS) m/z 384 (MH)⁺、401 (MNH₄)⁺。 24c. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- (5-hydroxypentyl)-, 1,1-dioxide

To a solution of the product of Example 24b (0.43 g, 1.0 mmol) in anhydrous THF (5 mL) was added 0.5 M AlH ₃ solution (5 mL, 2.5 mmol) and the reaction mixture was stirred at room temperature for 30 min under nitrogen. . The reaction mixture was quenched with saturated aqueous NH ₄ Cl and then acidified. After removal of the solvent under reduced pressure, the residue was partitioned between EtOAc and water, and the aqueous layer was further extracted with EtOAc (2 ×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent removed under reduced pressure. The resulting residue was purified by silica gel flash column chromatography eluting with 8% MeOH in CH ₂ Cl ₂ to give the title compound (0.37 g, 95% yield) as a white solid: mp 190 ° C;

Mass spectrum (API-TIS) m / z 384 (MH) ⁺ , 401 (MNH ₄ ) ⁺ .

表題の化合物を実施例1cの手順に従って、実施例24aの生成物および2-アミノ-6-(トリフルオロメチル)1,3-ベンゼンジスルホンアミドの反応により調製した。生成物を白色の泡状物(0.66 g, 収率21%)として得た:

質量スペクトル(API-TIS) m/z 460 (MH)⁺、477 (MNH₄)⁺。 Example 25: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- (5-hydroxypentyl) -6- (trifluoromethyl)-, 1,1- Dioxide
25a. 2H-1,2,4-Benzothiadiazine-3-pentanoic acid, 7- (aminosulfonyl) -3,4-dihydro-6- (trifluoromethyl)-, ethyl ester, 1,1-dioxide

The title compound was prepared by reaction of the product of Example 24a and 2-amino-6- (trifluoromethyl) 1,3-benzenedisulfonamide according to the procedure of Example 1c. The product was obtained as a white foam (0.66 g, 21% yield):

Mass spectrum (API-TIS) m / z 460 (MH) ⁺ , 477 (MNH ₄ ) ⁺ .

表題の化合物を実施例24cの手順に従って、実施例25aの生成物の還元により調製した。生成物を白色の固形物(0.34 g, 収率58%)として得た: mp 97℃ (収縮);

質量スペクトル(API-TIS) m/z 418 (MH)⁺、435 (MNH₄)⁺。 25b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- (5-hydroxypentyl) -6- (trifluoromethyl)-, 1,1-dioxide

The title compound was prepared by reduction of the product of Example 25a according to the procedure of Example 24c. The product was obtained as a white solid (0.34 g, 58% yield): mp 97 ° C. (shrinkage);

Mass spectrum (API-TIS) m / z 418 (MH) ⁺ , 435 (MNH ₄ ) ⁺ .

5-ヒドロキシ-1-ペンタナール(Acros Chemicals, 2.04 g, 20 mmol)および2-アミノ-6-クロロ-1,3-ベンゼンジスルホンアミド(2.87 g, 10 mmol)をジオキサン(75 mL)および濃塩酸(2 mL)の中で一緒に混合した。得られた混合物を1時間還流し、次いで室温に冷却し、飽和塩水で抽出し、有機層を分離し、溶媒を減圧で蒸発させた。得られた残留物を酢酸エチルで処理し、炭酸ナトリウム飽和水溶液、水、塩水で洗浄し、硫酸ナトリウムで乾燥し、ろ過し、ろ液を真空で濃縮して粗生成物を得た。シリカゲルのカラムクロマトグラフィーでの精製により、4%メタノールのジクロロメタン液で溶出させて白色の固形物0.9 gを得た。これは不要な生成物であった(471 (MH)⁺、および471 (MNH₄)⁺で分子イオンピーク)。10%メタノールのジクロロメタン液での溶出により得られたさらに極性の高い分画によって、表題の化合物(1.2 g, 収率32.5%)を白色の固形物として得た:mp 202-211℃;

質量スペクトル(API-TIS) m/z 387 (MNH₄)⁺、389 [(MNH₄) + 2]⁺。 Example 26: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- (4-hydroxybutyl)-, 1,1-dioxide

5-hydroxy-1-pentanal (Acros Chemicals, 2.04 g, 20 mmol) and 2-amino-6-chloro-1,3-benzenedisulfonamide (2.87 g, 10 mmol) were added to dioxane (75 mL) and concentrated hydrochloric acid ( Mixed together in 2 mL). The resulting mixture was refluxed for 1 hour, then cooled to room temperature, extracted with saturated brine, the organic layer was separated and the solvent was evaporated under reduced pressure. The resulting residue was treated with ethyl acetate, washed with saturated aqueous sodium carbonate, water, brine, dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give a crude product. Purification by silica gel column chromatography eluting with 4% methanol in dichloromethane gave 0.9 g of a white solid. This was an unwanted product (471 (MH) ⁺ and 471 (MNH ₄ ) ⁺ molecular ion peaks). A more polar fraction obtained by elution with 10% methanol in dichloromethane gave the title compound (1.2 g, 32.5% yield) as a white solid: mp 202-211 ° C .;

Mass spectrum (API-TIS) m / z 387 (MNH ₄ ) ⁺ , 389 [(MNH ₄ ) + 2] ⁺ .

2-アミノ-6-クロロ-1,3-ベンゼンジスルホンアミド(2.85 g, 10 mmol)のジオキサン(40 mL)懸濁液に、塩化5-ブロモバレリル(Aldrich Chemical Co., 1.4 mL, 1.05当量)を加えた。反応混合物を2時間還流した。溶媒を減圧で蒸発させ、残留物を5%酢酸エチルのエチルエーテルで摩砕して、表題の化合物を白色の固形物(4.39 g, 収率98%)として得た: mp > 220℃;

質量スペクトル(API-TIS) m/z 448 (MH)⁺、450 (MH + 2)⁺、465 (MNH₄)⁺、467 [(MNH₄) + 2]⁺。 Example 27: 4H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide
27a. Pentanamide, N- [2,4-bis (aminosulfonyl) -5-chlorophenyl] -5-bromo-

To a suspension of 2-amino-6-chloro-1,3-benzenedisulfonamide (2.85 g, 10 mmol) in dioxane (40 mL) was added 5-bromovaleryl chloride (Aldrich Chemical Co., 1.4 mL, 1.05 equivalents). added. The reaction mixture was refluxed for 2 hours. The solvent was evaporated under reduced pressure and the residue was triturated with 5% ethyl acetate in ethyl ether to give the title compound as a white solid (4.39 g, 98% yield): mp> 220 ° C .;

Mass spectrum (API-TIS) m / z 448 (MH) ⁺ , 450 (MH + 2) ⁺ , 465 (MNH ₄ ) ⁺ , 467 [(MNH ₄ ) + 2] ⁺ .

実施例27aの生成物(1.12 g, 2.6 mmol)をアセトニトリル(50 mL)に溶解した。この溶液に硝酸銀(0.265 g, 1.56 mmol, 1.4当量)を加え、得られた混合物を窒素雰囲気下で2時間還流した。ろ過後、溶媒を減圧下で蒸発させ、残留物を酢酸エチルで抽出し、水、塩水で洗浄し、硫酸ナトリウムで乾燥した。生成物をシリカゲルのカラムクロマトグラフィーにより、4%メタノールのジクロロメタン液で溶出させて精製し、表題の化合物(0.64 g, 収率57%)を白色の固形物として得た: mp 187-189℃;

質量スペクトル(API-TIS) m/z 431 (MH)⁺、433 (MH + 2)⁺、448 (MNH₄)⁺、450 [(MNH₄) + 2]⁺。 27b. Pentanamide, N- [2,4-bis (aminosulfonyl) -5-chlorophenyl] -5- (nitrooxy)-

The product of Example 27a (1.12 g, 2.6 mmol) was dissolved in acetonitrile (50 mL). To this solution was added silver nitrate (0.265 g, 1.56 mmol, 1.4 eq) and the resulting mixture was refluxed for 2 hours under a nitrogen atmosphere. After filtration, the solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate, washed with water, brine and dried over sodium sulfate. The product was purified by column chromatography on silica gel eluting with 4% methanol in dichloromethane to give the title compound (0.64 g, 57% yield) as a white solid: mp 187-189 ° C .;

Mass spectrum (API-TIS) m / z 431 (MH) ⁺ , 433 (MH + 2) ⁺ , 448 (MNH ₄ ) ⁺ , 450 [(MNH ₄ ) + 2] ⁺ .

反応27bの生成物は、実施例20cに記載されている手順に従って表題の化合物に変換される。 27c. 4H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide

The product of reaction 27b is converted to the title compound according to the procedure described in Example 20c.

トリエチルアミン(0.88 mL, 6.3 mmol)を実施例15aの粗生成物(2.7 mmol)および実施例18aの生成物(1.01 g, 2.5 mmol)のアセトニトリル(50 mL)混合物に加え、室温で3時間撹拌した。反応混合物を減圧下で蒸発乾固した。残留物を3 N HCl (50 mL)と酢酸エチル(100 mL×2)との間で分配した。有機抽出液を水、塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮し、真空下で乾燥した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(1:1〜1:0の勾配、酢酸エチルでのR_f=0.1)で溶出させて分離し、表題の化合物を白色の固形物(0.24 g, 収率17%)として得た: mp >165 (分解);

質量スペクトル(API-TIS) m/z 546 (MH⁺)。C₁₉H₂₀ClN₅O₈S₂に対し算出された分析値: C, 41.80; H, 3.69; N, 12.83; 実測値: C, 41.77; H, 3.52; N, 12.58。 Example 28 Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6-chloro-1 '-[3-[(nitrooxy) methyl] Benzoyl]-, 1,1-dioxide

Triethylamine (0.88 mL, 6.3 mmol) was added to a mixture of the crude product of Example 15a (2.7 mmol) and the product of Example 18a (1.01 g, 2.5 mmol) in acetonitrile (50 mL) and stirred at room temperature for 3 hours. . The reaction mixture was evaporated to dryness under reduced pressure. The residue was partitioned between 3 N HCl (50 mL) and ethyl acetate (100 mL × 2). The organic extract was washed with water, brine, dried over Na ₂ SO ₄ , filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with EtOAc / hexane (1: 1 to 1: 0 gradient, R _f = 0.1 with ethyl acetate) to give the title compound as a white solid (0.24 g, Yield 17%): mp> 165 (decomposition);

Mass spectrum (API-TIS) m / z 546 (MH ⁺ ). Calculated for C ₁₉ H ₂₀ ClN ₅ O ₈ S ₂ : C, 41.80; H, 3.69; N, 12.83; Found: C, 41.77; H, 3.52; N, 12.58.

表題の化合物を実施例5aの手順に従うことによって、アセトニトリル(50 mL)中AgNO₃ (4.06 g, 24 mmol)および2-(4-(ブロモメチル)フェニル)酢酸(5 g, 21.8 mmol)を用い白色の固形物(3.4 g, 収率74%)として調製した: mp 110℃;

質量スペクトル(API-TIS) m/z 229 (MNH₄ ⁺)、211 (M-H)。 Example 29: 4H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3-[[4-[(nitrooxy) methyl] phenyl] methyl]-, 1,1-dioxide
29a. Benzeneacetic acid, 4-[(nitrooxy) methyl]-

Follow the procedure of Example 5a with the title compound using AgNO ₃ (4.06 g, 24 mmol) and 2- (4- (bromomethyl) phenyl) acetic acid (5 g, 21.8 mmol) in acetonitrile (50 mL). Prepared as a solid (3.4 g, 74% yield): mp 110 ° C .;

Mass spectrum (API-TIS) m / z 229 (MNH ₄ ⁺ ), 211 (MH).

表題の化合物を、実施例20aの手順に従うことにより、CH₂Cl₂ (10 mL)中にて実施例29aの生成物(1.5 g, 7.1 mmol)、塩化オキサリル(0.95 mL, 1.35 g, 10.7 mmol)およびDMF (35 μL)から定量的な収率の吸湿性固形物として調製した。

質量スペクトル(API-TIS) m/z 229 (MH⁺)。 29b. Benzeneacetyl chloride, 4-[(nitrooxy) methyl]-

The product of Example 29a (1.5 g, 7.1 mmol), oxalyl chloride (0.95 mL, 1.35 g, 10.7 mmol) was obtained in CH ₂ Cl ₂ (10 mL) by following the procedure for Example 20a. ) And DMF (35 μL) as a hygroscopic solid in quantitative yield.

Mass spectrum (API-TIS) m / z 229 (MH ⁺ ).

表題の化合物を、実施例20bの手順に従うことにより、ジオキサン(10 mL)中にて実施例29bの生成物(7.1 mmol)および4-クロロ-6-アミノベンゼン-1,3-ジスルホンアミド(1.61 g, 5.68 mmol)から白色の固形物(2.2 g, 収率81%)として調製した。Mp 163-165℃。

質量スペクトル (API-TIS) m/z 477 (M-H)、479 (MH⁺)、496 (MNH₄ ⁺)、501 (MNa⁺)。 29c. N- (5-Chloro-2,4-disulfamoylphenyl) -2- {4-[(nitrooxy) methyl] phenyl} acetamide

The title compound was obtained by following the procedure of Example 20b in dioxane (10 mL) with the product of Example 29b (7.1 mmol) and 4-chloro-6-aminobenzene-1,3-disulfonamide (1.61 g, 5.68 mmol) as a white solid (2.2 g, 81% yield). Mp 163-165 ° C.

Mass spectrum (API-TIS) m / z 477 (MH), 479 (MH ⁺ ), 496 (MNH ₄ ⁺ ), 501 (MNa ⁺ ).

表題の化合物を、実施例20cの手順に従うことにより、水(9 mL)中にて実施例29cの生成物(0.7 g, 1.5 mmol)およびNaOH (0.12 g, 3 mmol)から白色の固形物(0.1 g, 収率13%)として調製した。Mp >260℃;

質量スペクトル(API-TIS) m/z 459 (M-H)、461 (MH⁺)、478 (MNH₄ ⁺)。 29d. 4H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3-[[4-[(nitrooxy) methyl] phenyl] methyl]-, 1,1-dioxide

The title compound was purified from the product of Example 29c (0.7 g, 1.5 mmol) and NaOH (0.12 g, 3 mmol) in white (9 mL) by following the procedure of Example 20c (9 mL). 0.1 g, yield 13%). Mp> 260 ° C;

Mass spectrum (API-TIS) m / z 459 (MH), 461 (MH ⁺ ), 478 (MNH ₄ ⁺ ).

実施例5aの生成物(3.54 g, 20 mmol)、N-(3-ジメチルアミノプロピル)-N'-エチルカルボジイミド塩酸塩(3.83 g, 20 mmol)、1-ヒドロキシベンゾトリアゾール水和物(2.70 g, 20 mmol)、および実施例18aの生成物(8.05 g, 20 mmol)のアセトニトリル(120 mL)液に、トリエチルアミン(18.36 mL, 132 mmol)を加えた。得られた混合物を室温で7時間撹拌し、濃縮して揮発性物質を除去し、EtOAcで処理し、水、NaHCO₃水溶液、およびNaCl水溶液で洗浄した。有機層をNa₂SO₄で乾燥し、ろ過し、濃縮して固形物を得た。粗生成物のクロマトグラフィー(シリカゲル、負荷の場合THF、溶出の場合EtOAc)とそれに続くTHF:EtOAc (5:1)からの再結晶により、表題の化合物(3.60 g, 収率34%)を白色の針状結晶として得た: mp 159-162℃ (分解);

質量スペクトル(API-TIS) m/z 526.4および528.3 (それぞれ³⁵Clおよび³⁷ClのMH⁺)。 Example 30: Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6-chloro-1 '-[6- (nitrooxy) -1 -Oxohexyl]-, 1,1-dioxide

Product of Example 5a (3.54 g, 20 mmol), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (3.83 g, 20 mmol), 1-hydroxybenzotriazole hydrate (2.70 g Triethylamine (18.36 mL, 132 mmol) was added to a solution of the product of Example 18a (8.05 g, 20 mmol) in acetonitrile (120 mL). The resulting mixture was stirred at room temperature for 7 hours, concentrated to remove volatiles, treated with EtOAc, washed with water, aqueous NaHCO ₃ , and aqueous NaCl. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give a solid. Chromatography of the crude product (silica gel, THF for loading, EtOAc for elution) followed by recrystallization from THF: EtOAc (5: 1) gave the title compound (3.60 g, 34% yield) in white Obtained as acicular crystals of: mp 159-162 ° C (decomposition);

Mass spectrum (API-TIS) m / z 526.4 and 528.3 ( ³⁵ Cl and ³⁷ Cl MH ^+, respectively).

表題の化合物を米国特許第4,616,012号の実施例7bに記載のように調製した。 Example 31: 2H-1,2,4-benzothiadiazine-2-acetic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, (2R) -2,3-bis (nitrooxy) ) Propyl ester, 1,1-dioxide
31a. 2H-1,2,4-Benzothiadiazine-2-acetic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, 1,1-dioxide

The title compound was prepared as described in Example 7b of US Pat. No. 4,616,012.

実施例31aの生成物(1.423 g, 4.0 mmol)および((2R)-3-ヒドロキシプロパン-1,2-ジイルジニトレート) (0.874 g, 4.8 mmol, 米国特許第2004/0024057号の実施例5dに従って調製)のDMF 25 mL溶液に、N,N-ジメチルアミノピリジン(DMAP, 0.098 g, 0.8 mmol)および1-(3-(ジメチルアミノ)プロピル)-3-エチルカルボジイミド塩酸塩(EDAC, 0.920 g, 4.8 mmol)を加えた。反応混合物を室温で16時間撹拌した。減圧下での溶媒の蒸発後、残留物を酢酸エチルと水との間で分配した。有機層を塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒の蒸発後、残留物をシリカゲル、ジクロロメタン中50〜90%酢酸エチル勾配のカラムクロマトグラフィーにより精製した。溶媒の蒸発により、表題の化合物(0.88 g, 収率42%)を白色の無定形固体として得た:

質量スペクトル(API-TIS) m/z 537 (MNH₄ ⁺)、1056 (2MNH₄ ⁺)。 31b. 2H-1,2,4-Benzothiadiazine-2-acetic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, (2R) -2,3-bis (nitrooxy) propyl Ester, 1,1-dioxide

The product of Example 31a (1.423 g, 4.0 mmol) and ((2R) -3-hydroxypropane-1,2-diyl dinitrate) (0.874 g, 4.8 mmol, Example 5d of US 2004/0024057) Prepared in DMF in 25 mL solution was added N, N-dimethylaminopyridine (DMAP, 0.098 g, 0.8 mmol) and 1- (3- (dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (EDAC, 0.920 g , 4.8 mmol). The reaction mixture was stirred at room temperature for 16 hours. After evaporation of the solvent under reduced pressure, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel, 50-90% ethyl acetate gradient in dichloromethane. Evaporation of the solvent gave the title compound (0.88 g, 42% yield) as a white amorphous solid:

Mass spectrum (API-TIS) m / z 537 (MNH ₄ ⁺ ), 1056 (2MNH ₄ ⁺ ).

ヒドロクロロチアジド(ONBIO, Inc., Ontario, Canada) (13.82 g, 46.4 mmol)のDMF (50 mL)溶液に、炭酸セシウム(7.51 g, 23.0 mmol)およびブロモ酢酸エチル(7.69 g, 46.1 mmol)を加え、混合物を室温で18時間撹拌した。固形物を吸引ろ過によって除去し、溶媒を真空下で蒸発させた。得られた残留物を酢酸エチルと水との間で分配し、有機層を水および塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒の除去後、残留物を酢酸エチル/エーテルから再結晶して、表題の生成物(10.9 g, 収率61%)を白色の針状結晶として得た: mp 199-203℃;

質量スペクトル(API-TIS) m/z 384 (MH⁺)、401 (MNH₄ ⁺)、784 (2MNH₄ ⁺)。 Example 32: 6-Chloro-2- (2-hydroxyethyl) -3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide
32a. 2H-1,2,4-Benzothiadiazine-2-acetic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, ethyl ester, 1,1-dioxide

To a solution of hydrochlorothiazide (ONBIO, Inc., Ontario, Canada) (13.82 g, 46.4 mmol) in DMF (50 mL) was added cesium carbonate (7.51 g, 23.0 mmol) and ethyl bromoacetate (7.69 g, 46.1 mmol). The mixture was stirred at room temperature for 18 hours. The solid was removed by suction filtration and the solvent was evaporated under vacuum. The resulting residue was partitioned between ethyl acetate and water and the organic layer was washed with water and brine and dried over magnesium sulfate. After removal of the solvent, the residue was recrystallized from ethyl acetate / ether to give the title product (10.9 g, 61% yield) as white needles: mp 199-203 ° C .;

Mass spectrum (API-TIS) m / z 384 (MH ⁺ ), 401 (MNH ₄ ⁺ ), 784 (2MNH ₄ ⁺ ).

実施例32aの生成物(4.10 g, 10.68 mmol)のTHF 70 mL溶液に、室温でメタノール0.3 mL、続いて水素化ホウ素リチウム(THF中2.0 M, 10.68 mmol, 5.3 mL)を加えた。30分後、水素化ホウ素リチウムをさらに2 mL加えた。さらに30分後、反応をメタノールおよび水でクエンチングした。反応混合物を減圧下で濃縮し、残留物を酢酸エチルと水との間で分配した。水層のpHを7〜8に調整し、この層を除去した。有機層を水および塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒の蒸発後、残留物をアセトン/ヘキサンから再結晶して、表題の生成物(2.784 g, 収率76%)を白色の多角柱状結晶として得た: mp 226-228℃;

質量スペクトル(API-TIS) m/z 342 (MH⁺)、359 (MNH₄ ⁺)、700 (2MNH₄ ⁺)。 32b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- (2-hydroxyethyl)-, 1,1-dioxide

To a solution of the product of Example 32a (4.10 g, 10.68 mmol) in 70 mL of THF at room temperature was added 0.3 mL of methanol followed by lithium borohydride (2.0 M in THF, 10.68 mmol, 5.3 mL). After 30 minutes, an additional 2 mL of lithium borohydride was added. After an additional 30 minutes, the reaction was quenched with methanol and water. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The pH of the aqueous layer was adjusted to 7-8 and this layer was removed. The organic layer was washed with water and brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from acetone / hexane to give the title product (2.784 g, 76% yield) as white polygonal crystals: mp 226-228 ° C .;

Mass spectrum (API-TIS) m / z 342 (MH ⁺ ), 359 (MNH ₄ ⁺ ), 700 (2MNH ₄ ⁺ ).

10〜15℃で維持された実施例32aの生成物(4.10 g, 10.68 mmol)のTHF 20 mLおよびエタノール11.5 mL撹拌溶液に、反応温度を25℃未満に保持するため、水素化ホウ素ナトリウムを分割して加えた。添加が完了してから30分後に、6 N HCl 3.75 mLを反応混合物にゆっくり加えて、温度を25℃未満に維持した。急冷された反応混合物を、セライトのパッドを通してろ過し、固形物をTHF/エタノール 1:1 (40 mL)の溶液で洗浄した。清澄な溶液を減圧下で濃縮し、残留物を酢酸エチルと水との間で分配した。水層のpHを7〜8に調整し、この層を除去した。有機層を水および塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒の蒸発後、残留物をアセトン/ヘキサンから再結晶して、表題の生成物(2.784 g, 収率76%)を白色の多角柱状結晶として得た: mp 226-228℃;

質量スペクトル(API-TIS) m/z 342 (MH⁺)、359 (MNH₄ ⁺)、700 (2MNH₄ ⁺)。 32c. Alternative synthesis of 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- (2-hydroxyethyl)-, 1,1-dioxide

Partition the sodium borohydride into a stirred solution of the product of Example 32a (4.10 g, 10.68 mmol) in 20 mL of THF and 11.5 mL of ethanol maintained at 10-15 ° C to keep the reaction temperature below 25 ° C. And added. 30 minutes after the addition was complete, 3.75 mL of 6 N HCl was slowly added to the reaction mixture to maintain the temperature below 25 ° C. The quenched reaction mixture was filtered through a pad of celite and the solid was washed with a solution of THF / ethanol 1: 1 (40 mL). The clear solution was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The pH of the aqueous layer was adjusted to 7-8 and this layer was removed. The organic layer was washed with water and brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from acetone / hexane to give the title product (2.784 g, 76% yield) as white polygonal crystals: mp 226-228 ° C .;

Mass spectrum (API-TIS) m / z 342 (MH ⁺ ), 359 (MNH ₄ ⁺ ), 700 (2MNH ₄ ⁺ ).

ヒドロクロロチアジド(3.80 g, 12.8 mmol)のDMF (60 mL)撹拌溶液に、炭酸セシウム(2.09 g, 6.4 mmol)およびα,α'-ジブロモ-m-キシレン(3.96 g, 15 mmol)を加えた。室温で20時間撹拌した後に、混合物を水に注ぎ入れ、EtOAcで抽出した。有機層を塩水で洗浄し、Na₂SO₄のパッドを通してろ過し、蒸発乾固した。得られた白色の固形物をアセトニトリル(80 mL)に溶解し、硝酸銀(8.50 g, 50 mmol)で処理し、室温で19時間撹拌した。混合物を濃縮して揮発性物質を除去した。残留物をEtOAcで処理し、その後NaCl水溶液とともに10分間撹拌した。ろ過後、有機層を分離し、Na₂SO₄のパッドを通してろ過し、濃縮した。粗生成物をクロマトグラフィー(シリカゲル、CH₂Cl₂中0〜50% EtOAc勾配)およびその後EtOAc:CH₂Cl₂ (1:3)からの再結晶により精製して、表題の化合物(1.57 g, 2段階での収率27%)を白色の固形物として得た: mp 136-139℃ (分解);

質量スペクトル(API-TIS) m/z 463.2および465.2 (それぞれ³⁵Clおよび³⁷ClのMH⁺)。 Example 33: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2-[[3-[(nitrooxy) methyl] phenyl] methyl]-, 1,1-dioxide

To a stirred solution of hydrochlorothiazide (3.80 g, 12.8 mmol) in DMF (60 mL) was added cesium carbonate (2.09 g, 6.4 mmol) and α, α'-dibromo-m-xylene (3.96 g, 15 mmol). After stirring at room temperature for 20 hours, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, filtered through a pad of Na ₂ SO ₄ and evaporated to dryness. The resulting white solid was dissolved in acetonitrile (80 mL), treated with silver nitrate (8.50 g, 50 mmol), and stirred at room temperature for 19 hours. The mixture was concentrated to remove volatiles. The residue was treated with EtOAc and then stirred with aqueous NaCl for 10 minutes. After filtration, the organic layer was separated, filtered through a pad of Na ₂ SO ₄ and concentrated. The crude product was purified by chromatography (silica gel, 0-50% EtOAc gradient in CH ₂ Cl ₂ ) followed by recrystallization from EtOAc: CH ₂ Cl ₂ (1: 3) to give the title compound (1.57 g, (2% yield 27%) was obtained as a white solid: mp 136-139 ° C. (decomposition);

Mass spectrum (API-TIS) m / z 463.2 and 465.2 ( ³⁵ Cl and ³⁷ Cl MH ^+, respectively).

実施例31aの生成物(0.767 g, 2.16 mmol)、3-(ニトロオキシ)プロピルアミン硝酸塩(0.426 g, 2.33 mmol, 国際公開公報第2005/030135 A2号, 実施例8aに記載のように調製)、DMAP (142 mg, 1.16 mmol)、EDAC (0.49 g, 2.56 mmol)およびNEt₃ (0.9 mL, 6.46 mmol)のDMF (30 mL)溶液を室温で一晩撹拌した。反応混合物を真空下で蒸発乾固した。残留物を3 N HCl (50 mL)とCH₂Cl₂ (100 mL)との間で分配した。有機抽出液を3 N HCl、水、塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮し、真空下で乾燥した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc (R_f=0.1)で溶出させて精製した。得られた固形物をEtOAcに溶解し、CHCl₃で摩砕した。固形物を集め、真空下で乾燥して表題の化合物を黄色の固形物(0.20 g, 収率20%)として得た: mp 138-141℃;

質量スペクトル(API-TIS) m/z 457 (M-H)^-。 Example 34: 2H-1,2,4-benzothiadiazine-2-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N- [3- (nitrooxy) propyl]-, 1,1-dioxide

Product of Example 31a (0.767 g, 2.16 mmol), 3- (nitrooxy) propylamine nitrate (0.426 g, 2.33 mmol, prepared as described in WO 2005/030135 A2, Example 8a), A solution of DMAP (142 mg, 1.16 mmol), EDAC (0.49 g, 2.56 mmol) and NEt ₃ (0.9 mL, 6.46 mmol) in DMF (30 mL) was stirred at room temperature overnight. The reaction mixture was evaporated to dryness under vacuum. The residue was partitioned between 3 N HCl (50 mL) and CH ₂ Cl ₂ (100 mL). The organic extract was washed with 3 N HCl, water, brine, dried over Na ₂ SO ₄ , filtered, concentrated and dried under vacuum. The product was purified by silica gel column chromatography eluting with EtOAc (R _f = 0.1). The resulting solid was dissolved in EtOAc and triturated with CHCl ₃ . The solid was collected and dried under vacuum to give the title compound as a yellow solid (0.20 g, 20% yield): mp 138-141 ° C .;

Mass spectrum (API-TIS) m / z 457 (MH) ^- .

硝酸(90%, 39 mL)を撹拌しながら0℃でAc₂O (98 mL)に分けて加えた。25分後、3-ブロモ-1-プロパノール(23 g, 165 mmol)のEtOAc (120 mL)液を加え、得られた混合物を同じ温度で50分間撹拌した。反応混合物を氷水/EtOAcの撹拌混合物に注ぎ入れ、NaHCO₃固形物を用いてpH 8に注意深く塩基性化した。有機層を分離し、NaHCO₃水溶液で洗浄し、Na₂SO₄のパッドを通してろ過し、濃縮し、手短に真空乾燥して表題の化合物(25.3 g, 収率84%)を液体として得た:

Example 35: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [3- (nitrooxy) propyl]-, 1,1-dioxide
35a. 1-Propanol, 3-Bromo-, Nitrate

Nitric acid (90%, 39 mL) was added in portions to Ac ₂ O (98 mL) at 0 ° C. with stirring. After 25 minutes, 3-bromo-1-propanol (23 g, 165 mmol) in EtOAc (120 mL) was added and the resulting mixture was stirred at the same temperature for 50 minutes. The reaction mixture was poured into a stirred mixture of ice water / EtOAc and carefully basified to pH 8 using NaHCO ₃ solid. The organic layer was separated, washed with aqueous NaHCO ₃ solution, filtered through a pad of Na ₂ SO ₄ , concentrated, and briefly dried in vacuo to give the title compound (25.3 g, 84% yield) as a liquid:

ヒドロクロロチアジド(41.1 g, 138 mmol)のDMF (400 mL)撹拌溶液に、炭酸セシウム(22.4 g, 68.75 mmol)および実施例35aの生成物(25.3 g, 137.5 mmol)を加えた。室温で22時間撹拌した後に、混合物を水に注ぎ入れ、EtOAcで抽出した。有機層をNaCl水溶液で洗浄し、Na₂SO₄のパッドを通してろ過し、濃縮した。粗生成物をクロマトグラフィー(シリカゲル、CH₂Cl₂中0〜25%勾配のEtOAc)およびその後EtOAc:CH₂Cl₂ (1:3)からの再結晶により精製して、表題の化合物(18.6 g, 収率34%)を白色の針状結晶として得た: mp 148-151℃ (分解)。

質量スペクトル(API-TIS) m/z 401.0および403.0 (それぞれ³⁵Clおよび³⁷ClのMH⁺)。C₁₀H₁₃ClN₄O₇S₂に対し算出された分析値: C, 29.97; H, 3.27; N, 13.98。実測値: C, 30.22; H, 2.93; N, 13.73。 35b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [3- (nitrooxy) propyl]-, 1,1-dioxide

To a stirred solution of hydrochlorothiazide (41.1 g, 138 mmol) in DMF (400 mL) was added cesium carbonate (22.4 g, 68.75 mmol) and the product of Example 35a (25.3 g, 137.5 mmol). After stirring at room temperature for 22 hours, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with aqueous NaCl, filtered through a pad of Na ₂ SO ₄ and concentrated. The crude product was purified by chromatography (silica gel, CH ₂ Cl ₂ in 0 to 25% EtOAc gradient) and then EtOAc: CH ₂ Cl _2: Purification by recrystallization from (1 3), the title compound (18.6 g , Yield 34%) was obtained as white needles: mp 148-151 ° C. (decomposition).

Mass spectrum (API-TIS) m / z 401.0 and 403.0 (MH ^{+ of 35} Cl and ³⁷ Cl, respectively). _{C 10 H 13 ClN 4 O 7} S 2 calculated analytical values for: C, 29.97; H, 3.27 ; N, 13.98. Found: C, 30.22; H, 2.93; N, 13.73.

120℃で4-クロロ-6-アミノベンゼン-1,3-ジスルホンアミド(Aldrich, 15.2 g, 53.3 mmol)およびブロモアセトアルデヒドジメチルアセタール(6.3 mL, 9 g, 53.3 mmol)の無水ジオキサン(45 mL)混合物に、48%臭化水素酸のH₂O (2 mL)を滴下した。次いで、混合物を100℃で20分間加熱した。溶媒の蒸発後、残留物を水で希釈し、得られた沈殿物をろ過し、水で洗浄して粘着性の固形物を得、これをEtOAcに溶解し、Na₂SO₄で乾燥した。溶媒の蒸発後の残留物をEtOAc/ヘキサンから再結晶して、定量的な収率の表題の化合物を白色の固形物として得た: mp 203-205℃;

質量スペクトル(API-TIS) m/z 387/389 (M-H)、407/409 (MNH₄ ⁺); C₈H₉BrClN₃O₄S₂・1/8モルEtOAcに対し算出された分析値: C, 25.41; H, 2.50; N, 10.46; 実測値: C, 25.35; H, 2.44; N, 10.46。 Example 36: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[[4- [2- (nitrooxy) ethyl] -1-piperidinyl ] Methyl]-, 1,1-dioxide, 2-hydroxy-1,2,3-propanetricarboxylate (1: 1) (salt)
36a. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- (bromomethyl) -6-chloro-3,4-dihydro-, 1,1-dioxide

A mixture of 4-chloro-6-aminobenzene-1,3-disulfonamide (Aldrich, 15.2 g, 53.3 mmol) and bromoacetaldehyde dimethyl acetal (6.3 mL, 9 g, 53.3 mmol) in anhydrous dioxane (45 mL) at 120 ° C 48% hydrobromic acid H ₂ O (2 mL) was added dropwise. The mixture was then heated at 100 ° C. for 20 minutes. After evaporation of the solvent, the residue was diluted with water and the resulting precipitate was filtered and washed with water to give a sticky solid that was dissolved in EtOAc and dried over Na ₂ SO ₄ . The residue after evaporation of the solvent was recrystallized from EtOAc / hexanes to give a quantitative yield of the title compound as a white solid: mp 203-205 ° C .;

Mass spectrum (API-TIS) m / z 387/389 (MH), 407/409 (MNH ₄ ⁺ ); Analytical value calculated for C ₈ H ₉ BrClN ₃ O ₄ S ₂ 1/8 mol EtOAc: C, 25.41; H, 2.50; N, 10.46; Found: C, 25.35; H, 2.44; N, 10.46.

室温でニトロオキシ(2-(4-ピペリジル)エチル)、硝酸塩(米国特許第2004/0024057号の実施例31aに記載のように調製, 1.46 g, 6.2 mmol)およびLiOH.H₂O (0.38 g, 8.9 mmol)のアセトン(12 mL)混合物を実施例36aの生成物(1.2 g, 3.1 mmol)で処理した。反応混合物を30分間還流した。溶媒の蒸発後の残留物をEtOAcに溶解し、水で洗浄し、Na₂SO₄で乾燥し、ろ過し、溶媒を蒸発させた。粗材料をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:EtOAc:MeOH (1:1:0.1)で溶出させて、表題の化合物(0.4 g, 収率26%)を白色の固形物として得た: mp 165-168℃;

質量スペクトル(API-TIS) m/z 482 (M-H)、484 (MH⁺); C₁₅H₂₂ClN₅O₇S₂・2モルH₂Oに対し算出された分析値: C, 34.65; H, 4.26; N, 13.46; 実測値: C, 35.02; H, 4.15; N, 13.04。 36b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[[4- [2- (nitrooxy) ethyl] -1-piperidinyl] methyl ]-, 1,1-dioxide

Nitrooxy (2- (4-piperidyl) ethyl), nitrate (prepared as described in Example 31a of US 2004/0024057, 1.46 g, 6.2 mmol) and LiOH.H ₂ O (0.38 g, at room temperature) A mixture of 8.9 mmol) of acetone (12 mL) was treated with the product of Example 36a (1.2 g, 3.1 mmol). The reaction mixture was refluxed for 30 minutes. The residue after evaporation of the solvent was dissolved in EtOAc, washed with water, dried over Na ₂ SO ₄ , filtered and the solvent was evaporated. The crude material was separated by chromatography on silica gel and eluted with CH ₂ Cl ₂ : EtOAc: MeOH (1: 1: 0.1) to give the title compound (0.4 g, 26% yield) as a white solid. : mp 165-168 ℃;

Mass spectrum (API-TIS) m / z 482 (MH), 484 (MH ⁺ ); Analytical value calculated for C ₁₅ H ₂₂ ClN ₅ O ₇ S ₂ · 2 mol H ₂ O: C, 34.65; H 4.26; N, 13.46; Found: C, 35.02; H, 4.15; N, 13.04.

MeOH (3 mL)中クエン酸(39.7 mg, 0.21 mmol)を実施例36bの生成物(0.1 g, 0.21 mmol)のEtOAc (3 mL)溶液に加えた。反応混合物を室温で5分間撹拌した。溶媒を蒸発させ、固形物をろ過し、EtOAcおよびヘキサンで洗浄して、表題の化合物(96 mg, 収率69%)をオフホワイト色の固形物として得た: mp 118℃;

質量スペクトル(API-TIS) m/z 482 (M-H)、484 (MH⁺); C₂₁H₃0ClN₅O₁₄S₂・1モルEtOAcに対し算出された分析値: C, 39.29; H, 5.00; N, 9.16; 実測値: C, 39.20; H, 4.86; N, 9.12。 36c. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[[4- [2- (nitrooxy) ethyl] -1-piperidinyl] methyl ]-, 1,1-dioxide, 2-hydroxy-1,2,3-propanetricarboxylate (1: 1) (salt)

Citric acid (39.7 mg, 0.21 mmol) in MeOH (3 mL) was added to a solution of the product of Example 36b (0.1 g, 0.21 mmol) in EtOAc (3 mL). The reaction mixture was stirred at room temperature for 5 minutes. The solvent was evaporated and the solid was filtered and washed with EtOAc and hexanes to give the title compound (96 mg, 69% yield) as an off-white solid: mp 118 ° C .;

Mass spectrum (API-TIS) m / z 482 (MH), 484 (MH +); C 21 H 3 0ClN 5 O 14 S 2 · 1 mol EtOAc calculated analytical values for: C, 39.29; H, 5.00 N, 9.16; Found: C, 39.20; H, 4.86; N, 9.12.

表題の化合物をDi Stilo et al, J. Med. Chem., 41: 5393-5401 (1998)により記載されているように実施例9aの生成物から無色の油状物(3.4 g, 収率65%)として調製した:

質量スペクトル(API-TIS) m/z 148 (MNH₄ ⁺)。 Example 37: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2-[(4-methyl-5-oxide-1,2,5- Oxadiazol-3-yl) methyl]-, 1,1-dioxide
37a. 1,2,5-oxadiazole-3-methanol, 4-methyl-, 5-oxide

The title compound was obtained from the product of Example 9a as described by Di Stilo et al, J. Med. Chem., 41: 5393-5401 (1998), as a colorless oil (3.4 g, 65% yield). ) Prepared as:

Mass spectrum (API-TIS) m / z 148 (MNH ₄ ⁺ ).

実施例37aの生成物(1.65 g, 12.7 mmol)のCH₂Cl₂ (33 mL)撹拌溶液に、ポリマー担持トリフェニルホスフィン(樹脂6.6 g, 3 mmolのP/g樹脂, 19.8 mmol)を加えた。混合物を窒素下にて室温で15分間撹拌した。この混合物に、四臭化炭素(5 g, 15.1 mmol)を分割して加えた。得られた混合物を室温で16時間撹拌した。固形物をろ過し、EtOAcで洗浄した。溶媒の蒸発後、残留物をシリカゲルのクロマトグラフィーにより分離しEtOAc:ヘキサン(1:6)で溶出させて、表題の化合物(1.7 g, 収率70%)を油状物として得た:

37b. 1,2,5-oxadiazole, 4- (bromomethyl) -3-methyl-, 2-oxide

To a stirred solution of the product of Example 37a (1.65 g, 12.7 mmol) in CH ₂ Cl ₂ (33 mL) was added polymer-supported triphenylphosphine (resin 6.6 g, 3 mmol P / g resin, 19.8 mmol). . The mixture was stirred at room temperature for 15 minutes under nitrogen. To this mixture, carbon tetrabromide (5 g, 15.1 mmol) was added in portions. The resulting mixture was stirred at room temperature for 16 hours. The solid was filtered and washed with EtOAc. After evaporation of the solvent, the residue was separated by chromatography on silica gel and eluted with EtOAc: hexane (1: 6) to give the title compound (1.7 g, 70% yield) as an oil:

実施例37bの生成物(0.1 g, 0.52 mmol)、ヒドロクロロチアジド(ONBIO Inc., 0.13 g, 0.43 mmol)およびK₂CO₃ (0.14 g, 1 mmol)のCH₃CN (1 mL)混合物を40〜60℃で2.5時間加熱した。粗反応混合物をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:EtOAc:MeOH (1:1:0.1)で溶出させて、表題の化合物(83 mg, 収率47%)を白色の固形物として得た: mp 235-237℃;

質量スペクトル(API-TIS) m/z 408 (M-H)、410 (MH⁺)、427 (MNH₄ ⁺)、432 (MNa⁺); C₁₁H₁₂ClN₅O₆S₂・1/2モルMeOHに対し算出された分析値: C, 32.50; H, 3.32; N, 16.47; 実測値: C, 32.32; H, 2.96; N, 16.18。 37c. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2-[(4-methyl-5-oxide-1,2,5-oxadi Azol-3-yl) methyl]-, 1,1-dioxide

A mixture of the product of Example 37b (0.1 g, 0.52 mmol), hydrochlorothiazide (ONBIO Inc., 0.13 g, 0.43 mmol) and K ₂ CO ₃ (0.14 g, 1 mmol) in CH ₃ CN (1 mL) Heated at 60 ° C. for 2.5 hours. The crude reaction mixture was separated by chromatography on silica gel and eluted with CH ₂ Cl ₂ : EtOAc: MeOH (1: 1: 0.1) to give the title compound (83 mg, 47% yield) as a white solid. T: mp 235-237 ° C;

Mass spectrum (API-TIS) m / z 408 (MH), 410 (MH ⁺ ), 427 (MNH ₄ ⁺ ), 432 (MNa ⁺ ); C ₁₁ H ₁₂ ClN ₅ O ₆ S ₂ 1/2 mol MeOH Analysis values calculated for: C, 32.50; H, 3.32; N, 16.47; Found: C, 32.32; H, 2.96; N, 16.18.

実施例31aの生成物(1.07 g, 3.0 mmol)および2-(メチルアミノ)エチルニトレートニトレート(2-(methylamino)ethyl nitrate nitrate) (0.549 g, 3.0 mmol, 米国特許第2004/0024057号, 実施例17cに従って調製)のDMF 30 mL溶液に、1-ヒドロキシベンゾトリアゾール(HOBt) (0.446 g, 3.3 mmol)およびEDAC (0.633 g, 3.3 mmol)を加えた。EDACが溶解した後に、トリエチルアミン(0.303 g, 3.0 mmol, 0.42 mL)を加え、混合物を室温で2時間撹拌した。溶媒を真空下で除去し、残留物を酢酸エチルと水との間で分配し、有機層を水および塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒の蒸発後、粗生成物をシリカゲルのカラムクロマトグラフィーにより酢酸エチル中0〜5%メタノール勾配で溶出させて精製した。溶媒の蒸発により、表題の化合物(0.30 g, 収率22%)を白色の固形物として得た: mp 160-165℃;

質量スペクトル(API-TIS) m/z 458 (MH⁺)、475 (MNH₄ ⁺)、915 (2MH⁺)、932 (2MNH₄ ⁺)。 Example 38: 2H-1,2,4-benzothiadiazine-2-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N-methyl-N- [2- (nitrooxy) Ethyl]-, 1,1-dioxide

The product of Example 31a (1.07 g, 3.0 mmol) and 2- (methylamino) ethyl nitrate nitrate (0.549 g, 3.0 mmol, U.S. Patent No. 2004/0024057, 1-Hydroxybenzotriazole (HOBt) (0.446 g, 3.3 mmol) and EDAC (0.633 g, 3.3 mmol) were added to a 30 mL DMF solution prepared according to Example 17c). After EDAC dissolved, triethylamine (0.303 g, 3.0 mmol, 0.42 mL) was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum, the residue was partitioned between ethyl acetate and water, the organic layer was washed with water and brine and dried over magnesium sulfate. After evaporation of the solvent, the crude product was purified by column chromatography on silica gel eluting with a 0-5% methanol gradient in ethyl acetate. Evaporation of the solvent gave the title compound (0.30 g, 22% yield) as a white solid: mp 160-165 ° C .;

Mass spectrum (API-TIS) m / z 458 (MH ⁺ ), 475 (MNH ₄ ⁺ ), 915 (2MH ⁺ ), 932 (2MNH ₄ ⁺ ).

実施例31aの生成物(1.07 g, 3.0 mmol)およびイミノジエタン-2,1-ジイルジニトレートニトレート(iminodiethane-2,1-diyl dinitrate nitrate) (0.774 g, 3.0 mmol, 本明細書の実施例49aに記載のように調製)のDMF 30 mL溶液に、1-ヒドロキシベンゾトリアゾール(HOBt) (0.446 g, 3.3 mmol)およびEDAC (0.633 g, 3.3 mmol)を加えた。EDACが溶解した後に、トリエチルアミン(0.303 g, 3.0 mmol, 0.42 mL)を加え、混合物を室温で2時間撹拌した。溶媒を真空下で除去し、残留物を酢酸エチルと水との間で分配し、有機層を水および塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒の蒸発後、粗生成物をシリカゲルのカラムクロマトグラフィーにより酢酸エチルで溶出させて精製した。溶媒の蒸発により、表題の化合物(0.20 g, 収率13%)を白色の無定形固体として得た:

質量スペクトル(API-TIS) m/z 533 (MH⁺)、550 (MNH₄ ⁺)。 Example 39: 2H-1,2,4-benzothiadiazine-2-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N, N-bis [2- (nitrooxy) ethyl ]-, 1,1-dioxide

The product of Example 31a (1.07 g, 3.0 mmol) and iminodiethane-2,1-diyl dinitrate nitrate (0.774 g, 3.0 mmol, Example 49a herein) 1-hydroxybenzotriazole (HOBt) (0.446 g, 3.3 mmol) and EDAC (0.633 g, 3.3 mmol) were added to a 30 mL DMF solution prepared as described in 1). After EDAC dissolved, triethylamine (0.303 g, 3.0 mmol, 0.42 mL) was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum, the residue was partitioned between ethyl acetate and water, the organic layer was washed with water and brine and dried over magnesium sulfate. After evaporation of the solvent, the crude product was purified by silica gel column chromatography eluting with ethyl acetate. Evaporation of the solvent gave the title compound (0.20 g, 13% yield) as a white amorphous solid:

Mass spectrum (API-TIS) m / z 533 (MH ⁺ ), 550 (MNH ₄ ⁺ ).

表題の化合物をJ. Med. Chem. 1993, 36, 815-819に記載のように調製した。 Example 40: 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [4- (nitrooxy) butyl]-, 1,1-dioxide
40a. 1-Butanol, 4-Bromo-, Nitrate

The title compound was prepared as described in J. Med. Chem. 1993, 36, 815-819.

表題の化合物を実施例35bの手順に従うことにより、ヒドロクロロチアジド(5.95 g, 20 mmol)、炭酸カリウム(1.38 g, 10 mmol)、および実施例40aの生成物(4.30 g, 21.8 mmol)から白色の多角柱状結晶(1.26 g, 収率15%)として合成した: mp 75-77℃;

質量スペクトル(API-TIS) m/z 415.2および417.1 (それぞれ³⁵Clおよび³⁷ClのMH⁺); C₁₁H₁₅ClN₄O₇S₂に対し算出された分析値: C, 31.85; H, 3.64; N, 13.51; 実測値: C, 32.31; H, 3.32; N, 13.37。 40b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [4- (nitrooxy) butyl]-, 1,1-dioxide

By following the procedure of Example 35b, the title compound was obtained from hydrochlorothiazide (5.95 g, 20 mmol), potassium carbonate (1.38 g, 10 mmol), and the product of Example 40a (4.30 g, 21.8 mmol) as a white polygon. Synthesized as columnar crystals (1.26 g, 15% yield): mp 75-77 ° C .;

Mass spectrum (API-TIS) m / z 415.2 and 417.1 (each ³⁵ Cl and _{^{37 Cl MH +); C 11}} H 15 ClN 4 O 7 S 2 analysis calculated with respect to: C, 31.85; H, 3.64 N, 13.51; Found: C, 32.31; H, 3.32; N, 13.37.

ヒドロクロロチアジド(3.65 g, 12.3 mmol)のDMF (50 mL)撹拌溶液に、炭酸セシウム(2.00 g, 6.15 mmol)、および4-ブロモ-1-ブタノール(1.88 g, 12.3 mmol)を加えた。室温で22時間撹拌した後に、反応混合物を水に注ぎ入れ、EtOAcで抽出した。有機層をNaCl水溶液で洗浄し、Na₂SO₄のパッドを通してろ過し、濃縮した。クロマトグラフィー(シリカゲル; EtOAc、その後THFで溶出)およびその後EtOAc:ヘキサン(1:1)からの再結晶により、表題の化合物(0.66 g, 収率15%)を白色の固形物として得た: mp 96-99℃;

質量スペクトル(API-TIS) m/z 370.1および372.0 (それぞれ³⁵Clおよび³⁷ClのMH⁺)。 Example 41: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- (4-hydroxybutyl)-, 1,1-dioxide

To a stirred solution of hydrochlorothiazide (3.65 g, 12.3 mmol) in DMF (50 mL) was added cesium carbonate (2.00 g, 6.15 mmol) and 4-bromo-1-butanol (1.88 g, 12.3 mmol). After stirring at room temperature for 22 hours, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with aqueous NaCl, filtered through a pad of Na ₂ SO ₄ and concentrated. Chromatography (silica gel; EtOAc, then eluted with THF) and then recrystallization from EtOAc: hexane (1: 1) gave the title compound (0.66 g, 15% yield) as a white solid: mp 96-99 ° C;

Mass spectrum (API-TIS) m / z 370.1 and 372.0 (MH ^{+ of 35} Cl and ³⁷ Cl, respectively).

実施例32bの生成物(3.32 g, 9.73 mmol)および実施例22aの生成物(2.61 g, 11.68 mmol)のDMF 25 mL液に、N,N-ジメチルアミノピリジン(DMAP, 0.234 g, 1.94 mmol)および1-(3-(ジメチルアミノ)プロピル)-3-エチルカルボジイミド塩酸塩(EDAC, 2.41 g, 12.6 mmol)を加えた。反応混合物を室温で18時間撹拌した。減圧下での溶媒の蒸発後、残留物を酢酸エチルと水との間で分配した。有機層を塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒の蒸発後、残留物をシリカゲル、ジクロロメタン中3〜20%メタノール勾配でのカラムクロマトグラフィーによって精製した。溶媒の蒸発により、表題の化合物(0.41 g, 収率8%)を白色の無定形固体として得た:

質量スペクトル(API-TIS) m/z 565 (MNH₄ ⁺)、1112 (2MNH₄ ⁺)。 Example 42: pentanoic acid, 4,5-bis (nitrooxy)-, 2- [7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4 -Benzothiadiazin-2-yl] ethyl ester

To a 25 mL DMF solution of the product of Example 32b (3.32 g, 9.73 mmol) and the product of Example 22a (2.61 g, 11.68 mmol), N, N-dimethylaminopyridine (DMAP, 0.234 g, 1.94 mmol) And 1- (3- (dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (EDAC, 2.41 g, 12.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. After evaporation of the solvent under reduced pressure, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel, a 3-20% methanol gradient in dichloromethane. Evaporation of the solvent gave the title compound (0.41 g, 8% yield) as a white amorphous solid:

Mass spectrum (API-TIS) m / z 565 (MNH ₄ ⁺ ), 1112 (2MNH ₄ ⁺ ).

4,5-ビス(ニトロオキシ)ペンタン-1-オール(1.88 g, 8.95 mmol, 国際公開公報第2005/030135 A2号, 実施例27dに記載のように調製)のEt₂O (20 mL)溶液に、三臭化リン(0.844 mL, 8.95 mmol)を加えた。室温で16時間撹拌した後に、混合物を氷上に注ぎ、水で希釈し、Et₂Oで抽出した。有機層をNaHCO₃水溶液で洗浄し、Na₂SO₄のパッドを通してろ過し、濃縮した。クロマトグラフィー(1:5、その後1:3のEtOAc:ヘキサン、シリカゲル)により、表題の化合物(1.28 g, 収率52%)を無色の液体として得た:

Example 43: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 2- [4,5-bis (nitrooxy) pentyl] -6-chloro-3,4-dihydro-, 1,1 -Dioxide
43a. 1,2-Pentanediol, 5-bromo-, dinitrate

To a solution of 4,5-bis (nitrooxy) pentan-1-ol (1.88 g, 8.95 mmol, prepared as described in WO 2005/030135 A2, Example 27d) in Et ₂ O (20 mL) , Phosphorus tribromide (0.844 mL, 8.95 mmol) was added. After stirring at room temperature for 16 hours, the mixture was poured onto ice, diluted with water and extracted with Et ₂ O. The organic layer was washed with aqueous NaHCO ₃ solution, filtered through a pad of Na ₂ SO ₄ and concentrated. Chromatography (1: 5 then 1: 3 EtOAc: hexanes, silica gel) gave the title compound (1.28 g, 52% yield) as a colorless liquid:

表題の化合物を実施例35bの手順に従うことにより、ヒドロクロロチアジド(1.49 g, 5.00 mmol)、実施例43aの生成物(1.28 g, 4.70 mmol)、および炭酸セシウム(0.815 g, 2.50 mmol)から白色の固形物(1.66 g, 収率72%)として合成した: mp 49-53℃;

質量スペクトル(API-TIS) m/z 490.2および492.2 (それぞれ³⁵Clおよび³⁷ClのMH⁺)。 43b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [4,5-bis (nitrooxy) pentyl] -6-chloro-3,4-dihydro-, 1,1-dioxide

Follow the procedure of Example 35b for the title compound from hydrochlorothiazide (1.49 g, 5.00 mmol), the product of Example 43a (1.28 g, 4.70 mmol), and cesium carbonate (0.815 g, 2.50 mmol) to a white solid. Product (1.66 g, 72% yield): mp 49-53 ° C .;

Mass spectrum (API-TIS) m / z 490.2 and 492.2 (MH ^{+ of 35} Cl and ³⁷ Cl, respectively).

実施例32bの生成物(1.025 g, 3.0 mmol)および実施例4aの生成物(0.489 g, 3.0 mmol)のDMF 25 mLに、1-ヒドロキシベンゾトリアゾール(HOBt) (0.446 g, 3.3 mmol)およびEDAC (0.633 g, 3.3 mmol)を加えた。反応混合物を室温で18時間撹拌した。減圧下での溶媒の蒸発後、残留物を酢酸エチルと水との間で分配した。有機層を塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒の蒸発後、残留物をシリカゲルのカラムクロマトグラフィーによりジクロロメタン中0〜5%メタノール勾配で溶出させて精製した。溶媒の蒸発により、表題の化合物(0.08 g, 収率5%)を白色の無定形固体として得た:

質量スペクトル(API-TIS) m/z 504 (MNH₄ ⁺)、990 (2MNH₄ ⁺)。 Example 44: pentanoic acid, 5- (nitrooxy)-, 2- [7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothi Asiadin-2-yl] ethyl ester

To the DMF 25 mL of the product of Example 32b (1.025 g, 3.0 mmol) and the product of Example 4a (0.489 g, 3.0 mmol) was added 1-hydroxybenzotriazole (HOBt) (0.446 g, 3.3 mmol) and EDAC. (0.633 g, 3.3 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. After evaporation of the solvent under reduced pressure, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with a gradient of 0-5% methanol in dichloromethane. Evaporation of the solvent gave the title compound (0.08 g, 5% yield) as a white amorphous solid:

Mass spectrum (API-TIS) m / z 504 (MNH ₄ ⁺ ), 990 (2MNH ₄ ⁺ ).

室温でメチル[2-(ニトロオキシ)エチル]アミン、硝酸塩(米国特許第2004/0024057号, 実施例17cに記載のように調製, 72.6 mg, 0.39 mmol)、実施例36aの生成物(0.1 g, 0.25 mmol)およびK₂CO₃ (70.6 mg, 0.51 mmol)のCH₃CN (1 mL)混合物をLiOH.H₂O (30 mg, 0.71 mmol)で処理した。反応混合物を50℃で1時間加熱した。溶媒の蒸発後、残留物をEtOAcに溶解し、水で洗浄し、Na₂SO₄で乾燥し、ろ過し、溶媒を蒸発させた。粗材料をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:MeOH (1:0.1)で溶出させて、表題の化合物(50 mg, 収率45%)を白色の固形物として得た: mp 175-180℃;

質量スペクトル(API-TIS) m/z 427 (M-H)、430 (MH⁺)、452 (MNa⁺)。 Example 45: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[[methyl [2- (nitrooxy) ethyl] amino] methyl]- 1,1-dioxide

Methyl [2- (nitrooxy) ethyl] amine, nitrate (prepared as described in US Patent No. 2004/0024057, Example 17c, 72.6 mg, 0.39 mmol) at room temperature, the product of Example 36a (0.1 g, A mixture of CH ₃ CN (1 mL) of 0.25 mmol) and K ₂ CO ₃ (70.6 mg, 0.51 mmol) was treated with LiOH.H ₂ O (30 mg, 0.71 mmol). The reaction mixture was heated at 50 ° C. for 1 hour. After evaporation of the solvent, the residue was dissolved in EtOAc, washed with water, dried over Na ₂ SO ₄ , filtered and the solvent was evaporated. The crude material was separated by chromatography on silica gel and eluted with CH ₂ Cl ₂ : MeOH (1: 0.1) to give the title compound (50 mg, 45% yield) as a white solid: mp 175- 180 ° C;

Mass spectrum (API-TIS) m / z 427 (MH), 430 (MH ⁺ ), 452 (MNa ⁺ ).

表題の化合物を実施例35aの手順に従うことにより、5-ブロモ-1-ペンタノール(5.82 g, 35 mmol)から無色の液体(6.32 g, 収率86%)として調製した:

Example 46: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [5- (nitrooxy) pentyl]-, 1,1-dioxide
46a. 1-Pentanol, 5-bromo-, nitrate

The title compound was prepared from 5-bromo-1-pentanol (5.82 g, 35 mmol) as a colorless liquid (6.32 g, 86% yield) by following the procedure of Example 35a:

表題の化合物を実施例35bの手順により、ヒドロクロロチアジド(8.93 g, 30 mmol)、実施例46aの生成物(6.32 g, 29.9 mmol)、および炭酸セシウム(4.89 g, 15 mmol)から白色の固形物(8.72 g, 収率68%)として合成した: mp 120-123℃;

質量スペクトル(API-TIS) m/z 429.1および431.1 (それぞれ³⁵Clおよび³⁷ClのMH⁺); C₁₂H₁₇ClN₄O₇S₂に対し算出された分析値: C, 33.61; H, 4.00; N, 13.06; 実測値: C, 33.89; H, 3.74; N, 13.00。 46b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [5- (nitrooxy) pentyl]-, 1,1-dioxide

The title compound was prepared according to the procedure of Example 35b from hydrochlorothiazide (8.93 g, 30 mmol), the product of Example 46a (6.32 g, 29.9 mmol), and cesium carbonate (4.89 g, 15 mmol) to a white solid ( 8.72 g, 68% yield): mp 120-123 ° C;

Mass spectrum (API-TIS) m / z 429.1 and 431.1 (MH ⁺ of ³⁵ Cl and ³⁷ Cl respectively); calculated values for C ₁₂ H ₁₇ ClN ₄ O ₇ S ₂ : C, 33.61; H, 4.00 N, 13.06; Found: C, 33.89; H, 3.74; N, 13.00.

表題の化合物を実施例1aの手順に従うことにより、7-ブロモヘプタン-1-オール(5 g, 25.6 mmol)および硝酸銀(5.22 g, 30.7 mmol, 1.2当量)の反応によって無色の油状物(4.48 g, 99%)として得た:

質量スペクトル(API-TIS) m/z 178 (MH)⁺、195 (MNH₄)⁺。 Example 47: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [6- (nitrooxy) hexyl]-, 1,1-dioxide
47a. 1,7-Heptanediol, mononitrate

Following the procedure of Example 1a, the title compound was reacted with 7-bromoheptan-1-ol (5 g, 25.6 mmol) and silver nitrate (5.22 g, 30.7 mmol, 1.2 eq) as a colorless oil (4.48 g , 99%):

Mass spectrum (API-TIS) m / z 178 (MH) ⁺ , 195 (MNH ₄ ) ⁺ .

実施例47aの生成物(1.77 g, 10 mmol)を実施例1bの手順に従いジクロロメタン(50 mL)および水(0.2 mL)中Dess-Martinペルヨージナン試薬(4.17 g, 10 mmol)で処理して、表題の化合物を得た。得られた粗生成物をさらには精製せずに次の段階で用いた。 47b. Heptanal, 7- (Nitrooxy)-

The product of Example 47a (1.77 g, 10 mmol) was treated with Dess-Martin periodinane reagent (4.17 g, 10 mmol) in dichloromethane (50 mL) and water (0.2 mL) following the procedure of Example 1b to give the title The compound of The resulting crude product was used in the next step without further purification.

実施例47bの粗生成物(10 mmol)を実施例1cの手順に従ってジオキサン(100 mL)に溶解し、2-アミノ-6-クロロ-1,3-ベンゼンジスルホンアミド(1.43 g, 5 mmol)および濃塩酸(1.0 mL)で処理した。生成物をシリカゲルフラッシュクロマトグラフィーにより4%メタノールのジクロロメタン液で溶出させて精製し、表題の化合物(0.87 g, 収率39%)を白色の固形物として得た: mp 161℃;

質量スペクトル(API-TIS) m/z 443 (MH)⁺, 460 (MNH₄)⁺。 47c. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [6- (nitrooxy) hexyl]-, 1,1-dioxide

The crude product of Example 47b (10 mmol) was dissolved in dioxane (100 mL) according to the procedure of Example 1c and 2-amino-6-chloro-1,3-benzenedisulfonamide (1.43 g, 5 mmol) and Treated with concentrated hydrochloric acid (1.0 mL). The product was purified by flash chromatography on silica gel eluting with 4% methanol in dichloromethane to give the title compound (0.87 g, 39% yield) as a white solid: mp 161 ° C .;

Mass spectrum (API-TIS) m / z 443 (MH) ⁺ , 460 (MNH ₄ ) ⁺ .

この化合物を実施例43bの手順に従うことにより、(3S)-3,4-ビス(ニトロオキシ)ブタン-1-オール(1.36 g, 6.93 mmol, 国際公開公報第2005/030135 A2号, 実施例24dに記載のように調製)、および三臭化リン(1.90 g, 7 mmol)から液体(0.94 g, 収率53%)として合成した。

Example 48: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 2-[(3S) -3,4-bis (nitrooxy) butyl] -6-chloro-3,4-dihydro- 1,1-dioxide
48a. 1,2-Butanediol, 4-bromo-, dinitrate, (2S)-

By following the procedure of Example 43b for this compound (3S) -3,4-bis (nitrooxy) butan-1-ol (1.36 g, 6.93 mmol, WO 2005/030135 A2, Example 24d) Synthesized as described) and phosphorus tribromide (1.90 g, 7 mmol) as a liquid (0.94 g, 53% yield).

表題の化合物を実施例35bの手順に従うことにより、ヒドロクロロチアジド(1.19 g, 4 mmol)、実施例48aの生成物(0.94 g, 3.64 mmol)、および炭酸セシウム(0.593 g, 1.82 mmol)から白色の固形物(1.05 g, 2段階での収率32%)として合成した: mp 162-163℃;

質量スペクトル(API-TIS) m/z 476.1および478.1 (それぞれ³⁵Clおよび³⁷ClのMH⁺)。 48b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[(3S) -3,4-bis (nitrooxy) butyl] -6-chloro-3,4-dihydro-, 1 , 1-dioxide

Follow the procedure of Example 35b for the title compound from hydrochlorothiazide (1.19 g, 4 mmol), the product of Example 48a (0.94 g, 3.64 mmol), and cesium carbonate (0.593 g, 1.82 mmol) to a white solid. Product (1.05 g, 32% yield over 2 steps): mp 162-163 ° C .;

Mass spectrum (API-TIS) m / z 476.1 and 478.1 ( ^{35 +} and ³⁷ Cl MH ^+, respectively).

ジエタノールアミン(Aldrich, 5 g, 47.5 mmol)を-10℃で発煙HNO₃ (14.9 g, 9.9 mL, 0.24 mol)およびAc₂O (38.8 g, 36 mL, 0.38 mol)の混合物に滴下した。反応混合物を-10 ℃で5分間撹拌し、次いで氷冷EtOAc (50 mL)を加えた。反応混合物を-10℃で25分間さらに撹拌し、ヘキサンで希釈した。沈殿物をろ過により集め、ヘキサンで洗浄して、表題の化合物 (10.5 g, 86%)を白色の固形物として得た: mp 115-117℃;

質量スペクトル(API-TIS) m/z 196 (MH⁺); C₄H₁₀N₄O₉に対し算出された分析値: C, 18.61; H, 3.90; N, 21.70。実測値: C, 18.75; H, 3.67; N, 21.42。 Example 49: 2H-1,2,4-benzothiadiazine-3-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N, N-bis [2- (nitrooxy) ethyl ]-, 1,1-dioxide
49a. Ethanol, 2,2'-iminobis-, dinitrate (ester), nitrate (1: 1) (salt)

Diethanolamine (Aldrich, 5 g, 47.5 mmol) was added dropwise at −10 ° C. to a mixture of fuming HNO ₃ (14.9 g, 9.9 mL, 0.24 mol) and Ac ₂ O (38.8 g, 36 mL, 0.38 mol). The reaction mixture was stirred at −10 ° C. for 5 minutes and then ice-cold EtOAc (50 mL) was added. The reaction mixture was further stirred at −10 ° C. for 25 minutes and diluted with hexane. The precipitate was collected by filtration and washed with hexanes to give the title compound (10.5 g, 86%) as a white solid: mp 115-117 ° C .;

Mass spectrum (API-TIS) m / z 196 (MH ⁺ ); Calculated for C ₄ H ₁₀ N ₄ O ₉ : C, 18.61; H, 3.90; N, 21.70. Found: C, 18.75; H, 3.67; N, 21.42.

NaHCO₃飽和溶液を実施例49aの生成物(5 g, 19.4 mmol)のEtOAc (30 mL)撹拌懸濁液に滴下して、清澄な溶液を得た。有機相を飽和NaHCO₃、水で洗浄し、Na₂SO₄で乾燥し、ろ過し、真空で蒸発させて、表題の化合物(3.6 g, 収率95%)を黄白色の油状物として得、これを実施例49eの調製のためすぐに用いた。

質量スペクトル(API-TIS) m/z 196 (MH⁺)。 49b. Ethanol, 2,2'-iminobis-, dinitrate (ester)

A saturated solution of NaHCO ₃ was added dropwise to a stirred suspension of the product of Example 49a (5 g, 19.4 mmol) in EtOAc (30 mL) to give a clear solution. The organic phase was washed with saturated NaHCO ₃ , water, dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give the title compound (3.6 g, 95% yield) as a pale yellow oil, This was used immediately for the preparation of Example 49e.

Mass spectrum (API-TIS) m / z 196 (MH ⁺ ).

40℃で4-クロロ-6-アミノベンゼン-1,3-ジスルホンアミド(Aldrich, 14.1 g, 49.3 mmol)および3,3-ジメトキシプロピオン酸メチル(Aldrich, 9 mL, 9.4 g, 63.4 mmol)の無水ジオキサン(50 mL)混合物に、濃HCl (5 mL)を滴下した。次に、混合物を70〜90℃で30分間加熱した。溶媒を蒸発させ、固形物を水で洗浄し、EtOAcに溶解し、Na₂SO₄で乾燥した。溶媒の蒸発後、残留物をEtOAc/ヘキサンから再結晶して、定量的な収率の表題の化合物を白色の固形物として得た: mp 237-238℃;

質量スペクトル(API-TIS) m/z 367 (M-H)、370 (MH⁺)、387 (MNH₄ ⁺); C₁₀H₁₂ClN₃O₆S₂に対し算出された分析値: C, 32.48; H, 3.27; N, 11.36。実測値: C, 32.50; H, 3.09; N, 11.15。 49c. 2H-1,2,4-benzothiadiazine-3-acetic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, methyl ester, 1,1-dioxide

Anhydrous 4-chloro-6-aminobenzene-1,3-disulfonamide (Aldrich, 14.1 g, 49.3 mmol) and methyl 3,3-dimethoxypropionate (Aldrich, 9 mL, 9.4 g, 63.4 mmol) at 40 ° C Concentrated HCl (5 mL) was added dropwise to the dioxane (50 mL) mixture. The mixture was then heated at 70-90 ° C. for 30 minutes. The solvent was evaporated and the solid was washed with water, dissolved in EtOAc and dried over Na ₂ SO ₄ . After evaporation of the solvent, the residue was recrystallized from EtOAc / hexanes to give a quantitative yield of the title compound as a white solid: mp 237-238 ° C .;

Mass spectrum (API-TIS) m / z 367 (MH), 370 (MH ⁺ ), 387 (MNH ₄ ⁺ ); calculated for C ₁₀ H ₁₂ ClN ₃ O ₆ S ₂ : C, 32.48; H, 3.27; N, 11.36. Found: C, 32.50; H, 3.09; N, 11.15.

実施例49cの生成物(8.3 g, 22.4 mmol)および1 N NaOH (74 mL)のEtOH (265 mL)混合物を室温で1.5時間撹拌した。反応混合物を0℃に冷却し、1 N HCl (約80 mL)で酸性化した。溶媒を蒸発させ、得られた残留物をEtOAcで抽出し、水で洗浄し、Na₂SO₄で乾燥した。粗固形物をCH₂Cl₂:EtOAcから再結晶して、表題の化合物(6.2 g, 収率77%)を白色の固形物として得た: mp 160-162℃;

質量スペクトル(API-TIS) m/z 354 (M-H)、356 (MH⁺)、373 (MNH₄ ⁺); C₉H₁₀ClN₃O₆S₂に対し算出された分析値: C, 30.38; H, 2.83; N, 11.81。実測値: C, 30.61; H, 2.82; N, 11.47。 49d. 2H-1,2,4-benzothiadiazine-3-acetic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, 1,1-dioxide

A mixture of the product of Example 49c (8.3 g, 22.4 mmol) and 1 N NaOH (74 mL) in EtOH (265 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was cooled to 0 ° C. and acidified with 1 N HCl (˜80 mL). The solvent was evaporated and the resulting residue was extracted with EtOAc, washed with water and dried over Na ₂ SO ₄ . The crude solid was recrystallized from CH ₂ Cl ₂ : EtOAc to give the title compound (6.2 g, 77% yield) as a white solid: mp 160-162 ° C .;

Mass spectrum (API-TIS) m / z 354 (MH), 356 (MH ⁺ ), 373 (MNH ₄ ⁺ ); calculated for C ₉ H ₁₀ ClN ₃ O ₆ S ₂ : C, 30.38; H, 2.83; N, 11.81. Found: C, 30.61; H, 2.82; N, 11.47.

0℃でTHF (5 mL)およびDMF (3 mL)の混合液中の実施例49dの生成物(1 g, 2.81 mmol)および実施例49bの生成物(1.64 g, 8.4 mmol)の混合物を1-{3-(ジメチルアミノ)プロピル}-3-エチルカルボジイミド塩酸塩(0.64 g, 3.3 mmol)で処理した。反応混合物を0℃で3時間撹拌した。溶媒の蒸発後、残留物をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:EtOAc:MeOH (1:1:0.1)で溶出させて、表題の化合物(0.23 g, 収率15%)をオフホワイト色の固形物として得た: mp 94-97℃;

質量スペクトル(API-TIS) m/z 531 (M-H)、533 (MH⁺)、550 (MNH₄ ⁺); C₁₃H₁₇ClN₆O₁₁S₂に対し算出された分析値: C, 29.30; H, 3.22; N, 15.77; 実測値: C, 29.58; H, 3.13; N, 15.49。 49e. 2H-1,2,4-Benzothiadiazine-3-acetamide, 7- (Aminosulfonyl) -6-chloro-3,4-dihydro-N, N-bis [2- (nitrooxy) ethyl]- 1,1-dioxide

A mixture of the product of Example 49d (1 g, 2.81 mmol) and the product of Example 49b (1.64 g, 8.4 mmol) in a mixture of THF (5 mL) and DMF (3 mL) at 0 ° C. Treated with-{3- (dimethylamino) propyl} -3-ethylcarbodiimide hydrochloride (0.64 g, 3.3 mmol). The reaction mixture was stirred at 0 ° C. for 3 hours. After evaporation of the solvent, the residue was separated by chromatography on silica gel and eluted with CH ₂ Cl ₂ : EtOAc: MeOH (1: 1: 0.1) to give the title compound (0.23 g, 15% yield) off-white. Obtained as a colored solid: mp 94-97 ° C;

Mass spectrum (API-TIS) m / z 531 (MH), 533 (MH ⁺ ), 550 (MNH ₄ ⁺ ); calculated for C ₁₃ H ₁₇ ClN ₆ O ₁₁ S ₂ : C, 29.30; H, 3.22; N, 15.77; Found: C, 29.58; H, 3.13; N, 15.49.

ベンゼン-1,3,5-トリイルトリメタノール(2.3 g, 13.7 mmol, J. Org. Chem. 2001, 66, 5664に記載のように調製)のTHF (100 mL)溶液を発煙硝酸(2.6 mL, 55.7 mol)の無水酢酸(15 mL)のあらかじめ混合した溶液で処理し、室温で70分間撹拌した。水 (20 mL)を反応混合物に加え、THFを減圧下で蒸発させた。得られた混合物をEtOAc (100 mL×2)と水との間で分配した。合わせた有機抽出液を飽和NaHCO₃、塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(1:2, R_f=0.13)で溶出させて精製し、表題の化合物を清澄な油状物(1.18 g, 収率33%)として得た:

Example 50: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3- [3,5-bis [(nitrooxy) methyl] phenyl] -6-chloro-3,4-dihydro-, 1,1-dioxide
50a. 1,3,5-Benzenetrimethanol, 1,3-dinitrate

A THF (100 mL) solution of benzene-1,3,5-triyltrimethanol (2.3 g, 13.7 mmol, prepared as described in J. Org. Chem. 2001, 66, 5664) in fuming nitric acid (2.6 mL, Treated with a premixed solution of 55.7 mol) acetic anhydride (15 mL) and stirred at room temperature for 70 minutes. Water (20 mL) was added to the reaction mixture and THF was evaporated under reduced pressure. The resulting mixture was partitioned between EtOAc (100 mL × 2) and water. The combined organic extracts were washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc / hexane (1: 2, R _f = 0.13) to give the title compound as a clear oil (1.18 g, 33% yield):

クロロクロム酸ピリジニウム(1.20 g, 5.57 mmol)を実施例50aの生成物(1.295 g, 5.02 mmol)およびセライト(登録商標) (3.6 g)のCH₂Cl₂ (50 mL)混合物に加え、室温で15分間撹拌した。反応混合物を、セライト(登録商標)を通してろ過し、CH₂Cl₂ (100 mL)で洗浄した。ろ液を濃縮し、残留物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(1:3, R_f=0.25)で溶出させて精製し、表題の化合物を清澄な油状物(0.96 g, 収率75%)として得た:

質量スペクトル(API-TIS) m/z 274 (MNH₄)⁺。 50b. Benzaldehyde, 3,5-bis [(nitrooxy) methyl]-

Pyridinium chlorochromate (1.20 g, 5.57 mmol) was added to a mixture of the product of Example 50a (1.295 g, 5.02 mmol) and Celite® (3.6 g) in CH ₂ Cl ₂ (50 mL) at room temperature. Stir for 15 minutes. The reaction mixture was filtered through Celite® and washed with CH ₂ Cl ₂ (100 mL). The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with EtOAc / hexane (1: 3, R _f = 0.25) to give the title compound as a clear oil (0.96 g, 75% yield). Got as:

Mass spectrum (API-TIS) m / z 274 (MNH ₄ ) ⁺ .

実施例50bの生成物(0.71 g, 2.77 mmol)、4-アミノ-6-クロロベンゼン-1,3-ジスルホンアミド(0.78 g, 2.73 mmol)およびp-トルエンスルホン酸一水和物(0.311 g, 1.63 mmol)の1,4-ジオキサン(25 mL)溶液を100℃に4時間加熱した。反応混合物を濃縮し、得られた材料をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(3:2, R_f=0.6)で溶出させて分離した。粗材料をEtOAcに溶解し、CHCl₃で摩砕した。固形物を集め、真空下で乾燥して、表題の化合物を黄色の固形物(0.30 g, 収率21%)として得た: mp 121-124℃;

質量スペクトル(API-TIS) m/z 541 (MNH₄)⁺。C₁₅H₁₄ClN₅O₁₀S₂に対し算出された分析値: C, 34.39; H, 2.69; N, 13.37; 実測値: C, 34.24; H, 2.46; N, 13.11。 50c. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- [3,5-bis [(nitrooxy) methyl] phenyl] -6-chloro-3,4-dihydro-, 1, 1-dioxide

The product of Example 50b (0.71 g, 2.77 mmol), 4-amino-6-chlorobenzene-1,3-disulfonamide (0.78 g, 2.73 mmol) and p-toluenesulfonic acid monohydrate (0.311 g, 1.63 mmol) in 1,4-dioxane (25 mL) was heated to 100 ° C. for 4 h. The reaction mixture was concentrated and the resulting material was separated by silica gel column chromatography eluting with EtOAc / hexane (3: 2, R _f = 0.6). The crude material was dissolved in EtOAc and triturated with CHCl ₃ . The solid was collected and dried under vacuum to give the title compound as a yellow solid (0.30 g, 21% yield): mp 121-124 ° C .;

Mass spectrum (API-TIS) m / z 541 (MNH ₄ ) ⁺ . Calculated for C ₁₅ H ₁₄ ClN ₅ O ₁₀ S ₂ : C, 34.39; H, 2.69; N, 13.37; Found: C, 34.24; H, 2.46; N, 13.11.

トリフルオロ酢酸(4.9 mL, 63.60 mmol)を実施例32bの生成物(10.68 g, 31.23 mmol)のTHF (400 mL)溶液に加え、引き続いて発煙硝酸(4.4 mL, 94.27 mmol)の無水酢酸(45 mL)のあらかじめ混合した溶液の添加を行い、室温で2時間撹拌した。反応物を水(100 mL)に注ぎ入れ、飽和NaHCO₃でpHを約8に調整した。THFを減圧下で蒸発させ、得られた水性混合物をEtOAc (450 mL)で抽出した。有機抽出液を水、3 N HCl、塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(3:2, R_f=0.3)で溶出させて精製し、表題の化合物を黄色の固形物(9.64 g, 収率80%)として得た; mp 161-163℃ (分解)。分析用の純粋なサンプルは、EtOAc中の生成物をCHCl₃で摩砕することで得られた。

質量スペクトル(API-TIS) m/z 404 (MNH₄)⁺。C₉H₁₁ClN₄O₇S₂に対し算出された分析値: C, 27.95; H, 2.87; N, 14.48; 実測値: C, 28.15; H, 2.86; N, 14.33。 Example 51: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [2- (nitrooxy) ethyl]-, 1,1-dioxide

Trifluoroacetic acid (4.9 mL, 63.60 mmol) was added to the product of Example 32b (10.68 g, 31.23 mmol) in THF (400 mL) followed by fuming nitric acid (4.4 mL, 94.27 mmol) in acetic anhydride (45 mL) premixed solution was added and stirred at room temperature for 2 hours. The reaction was poured into water (100 mL) and the pH was adjusted to about 8 with saturated NaHCO ₃ . THF was evaporated under reduced pressure and the resulting aqueous mixture was extracted with EtOAc (450 mL). The organic extract was washed with water, 3 N HCl, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc / hexane (3: 2, R _f = 0.3) to give the title compound as a yellow solid (9.64 g, 80% yield); mp 161-163 ℃ (decomposition). An analytical pure sample was obtained by triturating the product in EtOAc with CHCl ₃ .

Mass spectrum (API-TIS) m / z 404 (MNH ₄ ) ⁺ . Calculated for C ₉ H ₁₁ ClN ₄ O ₇ S ₂ : C, 27.95; H, 2.87; N, 14.48; Found: C, 28.15; H, 2.86; N, 14.33.

トリフルオロ酢酸(19.5 mL, 0.253 mol)を実施例32bの生成物(43.1 g, 0.126 mol)のTHF (1 L)溶液に加え、引き続いて発煙硝酸(17.8 mL, 0.381 mol)の無水酢酸(180 mL)のあらかじめ混合した溶液の添加を行い、室温で2時間撹拌した。水(300 mL)を反応物に加え、1時間撹拌した。THFを減圧下で蒸発させた。得られた残留物を激しく撹拌しながら20%エタノール(1 L)で1時間摩砕した。固形物を集め、真空下で乾燥して、表題の化合物を黄色の固形物(39.4 g, 収率81%)として得た; mp 161-163℃ (分解)。

質量スペクトル(API-TIS) m/z 404 (MNH₄)⁺。C₉H₁₁ClN₄O₇S₂に対し算出された分析値: C, 27.95; H, 2.87; N, 14.48; 実測値: C, 28.15; H, 2.85; N, 14.33。 51b. Alternative synthesis of 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [2- (nitrooxy) ethyl]-, 1,1-dioxide

Trifluoroacetic acid (19.5 mL, 0.253 mol) was added to the product of Example 32b (43.1 g, 0.126 mol) in THF (1 L), followed by fuming nitric acid (17.8 mL, 0.381 mol) in acetic anhydride (180 mL) was added in advance and stirred at room temperature for 2 hours. Water (300 mL) was added to the reaction and stirred for 1 hour. THF was evaporated under reduced pressure. The resulting residue was triturated with 20% ethanol (1 L) for 1 hour with vigorous stirring. The solid was collected and dried under vacuum to give the title compound as a yellow solid (39.4 g, 81% yield); mp 161-163 ° C. (dec).

Mass spectrum (API-TIS) m / z 404 (MNH ₄ ) ⁺ . Calculated for C ₉ H ₁₁ ClN ₄ O ₇ S ₂ : C, 27.95; H, 2.87; N, 14.48; Found: C, 28.15; H, 2.85; N, 14.33.

トリフルオロ酢酸(0.32 mL, 4.09 mmol)を実施例32bの生成物(0.70 g, 2.05 mmol)のTHF (30 mL)溶液に加え、引き続いて発煙硝酸(0.60 mL, 12.86 mmol)の無水酢酸(6 mL)のあらかじめ混合した溶液の添加を行い、室温で2時間撹拌した。水(2 mL)を反応混合物に加え、THFを減圧下で蒸発させた。得られた水性混合物をEtOAc (100 mL)で抽出した。有機抽出液を水、3 N HCl、塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(3:2, R_f=0.1)で溶出させて精製し、表題の化合物を黄色の固形物(0.27 g, 収率31%)として得た; mp 144℃ (分解);

質量スペクトル(API-TIS) m/z 449 (MNH₄)⁺。C₉H₁₀ClN₅O₉S₂に対し算出された分析値: C, 25.03; H, 2.33; N, 16.22; 実測値: C, 25.30; H, 2.30; N, 15.95。 Example 52: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-4-nitro-2- [2- (nitrooxy) ethyl]-, 1, 1-dioxide

Trifluoroacetic acid (0.32 mL, 4.09 mmol) was added to the product of Example 32b (0.70 g, 2.05 mmol) in THF (30 mL) followed by fuming nitric acid (0.60 mL, 12.86 mmol) in acetic anhydride (6 mL) premixed solution was added and stirred at room temperature for 2 hours. Water (2 mL) was added to the reaction mixture and THF was evaporated under reduced pressure. The resulting aqueous mixture was extracted with EtOAc (100 mL). The organic extract was washed with water, 3 N HCl, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc / hexane (3: 2, R _f = 0.1) to give the title compound as a yellow solid (0.27 g, 31% yield); mp 144 ° C (decomposition);

Mass spectrum (API-TIS) m / z 449 (MNH ₄ ) ⁺ . Calculated for C ₉ H ₁₀ ClN ₅ O ₉ S ₂ : C, 25.03; H, 2.33; N, 16.22; Found: C, 25.30; H, 2.30; N, 15.95.

Example 53: 2H-1,2,4-benzothiadiazine-2-butanoic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, 1,1-dioxide
Benzyl alcohol (Aldrich Chemical Company, Wisconsin) (6.29 g, 58.1 mmol) was added to a solution of 4-bromobutyryl chloride (Aldrich Chemical Company, Wisconsin) (10.27 g, 55.4 mmol) in 100 mL of dichloromethane. Subsequently, potassium carbonate (8.3 g, 60 mmol) was added in 4 portions. After 2 hours, water was added and the layers were separated. The organic layer was washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent gave the title compound (11.87 g, 83% yield) as a colorless oil:

質量スペクトル(API-TIS) m/z 474 (MH⁺)、491 (MNH₄ ⁺)、964 (2MNH₄ ⁺)。 53b. 4- [7- (Aminosulfonyl) -6-chloro-1,1-dioxide-3,4-dihydro-2H-1,2,4-benzothiadiazin-2-yl] butanoic acid benzyl hydrochlorothiazide ( ONBIO, Inc., Ontario, Canada) (8.62 g, 29 mmol) in 30 mL of DMF was added cesium carbonate (4.68 g, 14.4 mmol) and the product of Example 53a (7.39 g, 28.7 mmol) and the mixture Was stirred at room temperature for 18 hours. The solid was removed by filtration and the solvent was removed under vacuum. The residue was partitioned between ethyl acetate and water and the organic layer was washed with water and brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel, 10-75% ethyl acetate gradient in dichloromethane. Evaporation of the solvent gave the title compound (8.71 g, 64% yield) as a white amorphous solid:

Mass spectrum (API-TIS) m / z 474 (MH +), 491 (MNH 4 +), 964 (2MNH 4 +).

53c. 2H-1,2,4-ベンゾチアジアジン-2-ブタン酸, 7-(アミノスルホニル)-6-クロロ-3,4-ジヒドロ-, 1,1-ジオキシド
実施例53bの生成物(11.26 g, 23.76 mmol)を500 mL Parr(登録商標)容器中にて、1:1の酢酸エチル/テトラヒドロフラン250 mLに溶解した。炭素上のパラジウム(10% Pd/C, 1.0 g)を加え、混合物を15 psiの水素下で30分間振盪した。反応混合物を、セライトを通してろ過し、溶媒を真空下で除去して、粗生成物を白色の固体として得た。アセトン/エーテルからの再結晶により、表題の化合物(8.21 g, 収率90%)を白色の結晶として得た: mp 72-78℃;

質量スペクトル(API-TIS) m/z 384 (MH⁺)、401 (MNH₄ ⁺)、784 (2MNH₄ ⁺)。

53c. 2H-1,2,4-Benzothiadiazine-2-butanoic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, 1,1-dioxide The product of Example 53b ( 11.26 g, 23.76 mmol) was dissolved in 250 mL of 1: 1 ethyl acetate / tetrahydrofuran in a 500 mL Parr® container. Palladium on carbon (10% Pd / C, 1.0 g) was added and the mixture was shaken under 15 psi hydrogen for 30 minutes. The reaction mixture was filtered through celite and the solvent removed in vacuo to give the crude product as a white solid. Recrystallization from acetone / ether gave the title compound (8.21 g, 90% yield) as white crystals: mp 72-78 ° C .;

Mass spectrum (API-TIS) m / z 384 (MH ⁺ ), 401 (MNH ₄ ⁺ ), 784 (2MNH ₄ ⁺ ).

表題の化合物を米国特許第2,775,622号中の手順に従うことにより調製した。

Example 54: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) -3,3-bis [(nitrooxy) Methyl] butyl]-, 1,1-dioxide
54a. 2,2-Bis (hydroxymethyl) pentane-1,5-diol

The title compound was prepared by following the procedure in US Pat. No. 2,775,622.

実施例54aの生成物(1.0 g, 6.09 mmol)をピリジン(25 mL)に溶解し、0℃に冷却した。tert-ブチルクロロジフェニルシラン(Aldrich Chemical Co., 1.59 g, 5.79 mmol)を加え、室温にゆっくり加温しながら反応混合物を18時間撹拌した。ピリジンを真空で除去し、残留物を酢酸エチルに再溶解し、水 (20 mL)、3 M塩酸(40 mL)、および最後に塩水(20 mL)で洗浄した。有機層を硫酸ナトリウムで乾燥した。ろ過および真空での溶媒の除去により、表題の化合物 (2.3 g, 収率93%)を淡黄色の油状物として得た:

54b. 2- (3-{[tert-Butyl (diphenyl) silyl] oxy} propyl) -2- (hydroxymethyl) propane-1,3-diol

The product of Example 54a (1.0 g, 6.09 mmol) was dissolved in pyridine (25 mL) and cooled to 0 ° C. tert-Butylchlorodiphenylsilane (Aldrich Chemical Co., 1.59 g, 5.79 mmol) was added and the reaction mixture was stirred for 18 hours while slowly warming to room temperature. Pyridine was removed in vacuo and the residue was redissolved in ethyl acetate and washed with water (20 mL), 3 M hydrochloric acid (40 mL), and finally brine (20 mL). The organic layer was dried with sodium sulfate. Filtration and removal of the solvent in vacuo gave the title compound (2.3 g, 93% yield) as a pale yellow oil:

ジクロロメタン(60 mL)中でスラリーにされ、その後0℃に冷却された実施例54bの生成物(2.3 g, 5.71 mmol)に、0℃で硝酸(90%発煙, 2.2 g, 34.3 mmol)および無水酢酸(7.6 mL)の混合物を加えた。反応混合物を0℃で3時間撹拌し、100 gの氷上に直接注ぎ、一晩静置させた。有機層を分離し、硫酸ナトリウムで乾燥し、ろ過し、溶媒を真空で除去して、表題の化合物(2.6 g, 収率85%)を黄色の油状物として得た:

54c. 2- [3-[[(1,1-Dimethylethyl) diphenylsilyl] oxy] propyl] -2-[(nitrooxy) methyl] -1,3-propanediol 1,3-dinitrate

To the product of Example 54b (2.3 g, 5.71 mmol) slurried in dichloromethane (60 mL) and then cooled to 0 ° C., nitric acid (90% fuming, 2.2 g, 34.3 mmol) and anhydrous at 0 ° C. A mixture of acetic acid (7.6 mL) was added. The reaction mixture was stirred at 0 ° C. for 3 hours, poured directly onto 100 g of ice and allowed to stand overnight. The organic layer was separated, dried over sodium sulfate, filtered and the solvent removed in vacuo to give the title compound (2.6 g, 85% yield) as a yellow oil:

実施例54cの生成物(2.6 g, 4.85 mmol)をテトラヒドロフラン(50 mL)に溶解し、フッ化テトラ-n-ブチルアンモニウム(Aldrich Chemical Co., テトラヒドロフラン中1 M, 5.0 mmol)をすぐに加えた。反応混合物を室温で45分間撹拌し、次いでシリカゲルのクロマトグラフ分離にすぐにかけ10%〜50%酢酸エチル/ヘキサン勾配で溶出させた。表題の化合物(1.0 g, 収率71%)を黄色の固形物として得た:

質量スペクトル(API-TIS) m/z 317 (MNH₄ ⁺)。 54d. 1,5-pentanediol, 2,2-bis [(nitrooxy) methyl]-, 1-nitrate

The product of Example 54c (2.6 g, 4.85 mmol) was dissolved in tetrahydrofuran (50 mL) and tetra-n-butylammonium fluoride (Aldrich Chemical Co., 1 M in tetrahydrofuran, 5.0 mmol) was added immediately. . The reaction mixture was stirred at room temperature for 45 minutes and then immediately chromatographed on silica gel eluting with a 10% to 50% ethyl acetate / hexane gradient. The title compound (1.0 g, 71% yield) was obtained as a yellow solid:

Mass spectrum (API-TIS) m / z 317 (MNH ₄ ⁺ ).

実施例54dの生成物(1.1 g, 3.6 mmol)を室温でジクロロメタン30 mLに溶解した。セライト(登録商標) (4.5 g)を加え、引き続いて重クロム酸ピリジニウム(Aldrich Chemical Co., 4.5 g, 12.0 mmol)の添加を行った。反応混合物を20時間撹拌し、シリカゲルの短パッドを通してろ過し、酢酸エチル/ヘキサン(1:1)で洗浄した。溶媒を真空で除去して、表題の化合物を黄色の油状物として得、これをさらには精製せずにすぐ用いた:

54e. 5- (Nitrooxy) -4,4-bis [(nitrooxy) methyl] -pentanal

The product of Example 54d (1.1 g, 3.6 mmol) was dissolved in 30 mL of dichloromethane at room temperature. Celite® (4.5 g) was added followed by the addition of pyridinium dichromate (Aldrich Chemical Co., 4.5 g, 12.0 mmol). The reaction mixture was stirred for 20 hours, filtered through a short pad of silica gel and washed with ethyl acetate / hexane (1: 1). The solvent was removed in vacuo to give the title compound as a yellow oil that was used immediately without further purification:

実施例54eの生成物(524 mg, 1.84 mmol)を無水1,4-ジオキサン(10 mL)中で処理した。4-アミノ-6-クロロ-1,3-ベンゼンジスルホンアミド (Aldrich Chemical Co., 600 mg, 2.02 mmol)を加え、引き続いて濃塩酸(0.5 mL)の添加を行った。反応混合物を18時間加熱還流し、室温に冷却し、溶媒を真空で除去した。得られた残留物をシリカゲルのカラムクロマトグラフィーによりメタノール/ジクロロメタン勾配(0:100〜35:65)で溶出させて精製し、表題の化合物(460 mg, 収率44%)を黄色ガラス状の固形物として得た:

質量スペクトル(API-TIS) m/z 582 (MNH₄ ⁺)。 54f. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) -3,3-bis [(nitrooxy) methyl] Butyl]-, 1,1-dioxide

The product of Example 54e (524 mg, 1.84 mmol) was treated in anhydrous 1,4-dioxane (10 mL). 4-Amino-6-chloro-1,3-benzenedisulfonamide (Aldrich Chemical Co., 600 mg, 2.02 mmol) was added, followed by addition of concentrated hydrochloric acid (0.5 mL). The reaction mixture was heated to reflux for 18 hours, cooled to room temperature and the solvent removed in vacuo. The resulting residue was purified by column chromatography on silica gel eluting with a methanol / dichloromethane gradient (0: 100 to 35:65) to give the title compound (460 mg, 44% yield) as a yellow glassy solid Got as a thing:

Mass spectrum (API-TIS) m / z 582 (MNH ₄ ⁺ ).

実施例50bの生成物(1.09 g, 4.25 mmol)、4-アミノ-6-(トリフルオロメチル)ベンゼン-1,3-ジスルホンアミド(1.25 g, 3.92 mmol)およびp-トルエンスルホン酸一水和物(0.39 g, 2.05 mmol)の1,4-ジオキサン(40 mL)溶液を5時間加熱還流した。反応混合物を濃縮し、得られた材料をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(2:3, R_f=0.2)で溶出させて分離した。粗材料をEtOAcに溶解し、CHCl₃で摩砕した。固形物を集め、真空下で乾燥して、表題の化合物を黄色の固形物(1.06 g, 収率45%)として得た: mp >113℃ (分解);

質量スペクトル(API-TIS) m/z 575 (MNH₄)。C₁₆H₁₄F₃N₅O₁₀S₂に対し算出された分析値: C, 34.48; H, 2.53; N, 12.56; 実測値: C, 34.51; H, 2.30; N, 12.28。 Example 55: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3- [3,5-bis [(nitrooxy) methyl] phenyl] -3,4-dihydro-6- (trifluoro Methyl)-, 1,1-dioxide

The product of Example 50b (1.09 g, 4.25 mmol), 4-amino-6- (trifluoromethyl) benzene-1,3-disulfonamide (1.25 g, 3.92 mmol) and p-toluenesulfonic acid monohydrate A solution of (0.39 g, 2.05 mmol) in 1,4-dioxane (40 mL) was heated to reflux for 5 hours. The reaction mixture was concentrated and the resulting material was separated by silica gel column chromatography eluting with EtOAc / hexane (2: 3, R _f = 0.2). The crude material was dissolved in EtOAc and triturated with CHCl ₃ . The solid was collected and dried under vacuum to give the title compound as a yellow solid (1.06 g, 45% yield): mp> 113 ° C. (decomposition);

Mass spectrum (API-TIS) m / z 575 (MNH ₄ ). Calculated for C ₁₆ H ₁₄ F ₃ N ₅ O ₁₀ S ₂ : C, 34.48; H, 2.53; N, 12.56; Found: C, 34.51; H, 2.30; N, 12.28.

実施例54dの生成物(1.1 g, 3.7 mmol)を乾燥テトラヒドロフラン(15 mL)に溶解し、次に四臭化炭素(Aldrich Chemical Co., 3.1 g, 9.4 mmol)を加え、引き続きトリフェニルホスフィン(Aldrich Chemical Co., 1.5 g, 5.6 mmol)の添加を行った。発熱反応物を室温で2.5時間撹拌した。溶媒を真空で除去して黄色油状の残留物を得た。ヘキサンを残留物に加え、固形物をろ過により除去し、ろ液を真空で濃縮して黄色の油状物を得た。油状物をシリカゲルのクロマトグラフィーにより分離し酢酸エチル/ヘキサン勾配(5:95〜35:65)で溶出させた。表題の化合物(1.1 g, 収率81%)を淡黄色の油状物として得、これをゆっくり凝固した:

Example 56: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [5- (nitrooxy) -4,4-bis [(nitrooxy) Methyl] phenyl]-, 1,1-dioxide
56a. 2- (3-Bromopropyl) -2-[(nitrooxy) methyl] -1,3-propanediol 1,3-dinitrate

The product of Example 54d (1.1 g, 3.7 mmol) was dissolved in dry tetrahydrofuran (15 mL), then carbon tetrabromide (Aldrich Chemical Co., 3.1 g, 9.4 mmol) was added followed by triphenylphosphine ( Aldrich Chemical Co., 1.5 g, 5.6 mmol) was added. The exothermic reaction was stirred at room temperature for 2.5 hours. The solvent was removed in vacuo to give a yellow oily residue. Hexane was added to the residue, the solid was removed by filtration, and the filtrate was concentrated in vacuo to give a yellow oil. The oil was separated by chromatography on silica gel and eluted with an ethyl acetate / hexane gradient (5:95 to 35:65). The title compound (1.1 g, 81% yield) was obtained as a pale yellow oil that slowly solidified:

実施例56aの生成物(1.1 g, 3.0 mmol)をN,N-ジメチルホルムアミド(10 mL)に溶解した。6-クロロ-3,4-ジヒドロ-2H-1,2,4-ベンゾチアジアジン-7-スルホンアミド1,1-ジオキシド(ONBIO, 1.0 g, 3.3 mmol)を加え、引き続き炭酸セシウム(0.5 g, 1.5 mmol)を加え、得られた混合物を室温で48時間撹拌した。反応混合物を水100 mLに注ぎ入れ、酢酸エチル(20 mL×2)で抽出した。合わせた有機層を塩水で洗浄し、硫酸ナトリウムで乾燥し、ろ過し、溶媒を真空で除去して黄色の油状物を得た。メタノール/ジクロロメタン勾配(0:100〜35:65)を用いたカラムクロマトグラフィーにより、表題の化合物(0.8 g, 収率41%)を白色ガラス状の固形物として得た:

質量スペクトル(API-TIS) m/z 596 (MNH₄ ⁺)。 56b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [5- (nitrooxy) -4,4-bis [(nitrooxy) methyl] Phenyl]-, 1,1-dioxide

The product of Example 56a (1.1 g, 3.0 mmol) was dissolved in N, N-dimethylformamide (10 mL). 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide (ONBIO, 1.0 g, 3.3 mmol) was added followed by cesium carbonate (0.5 g 1.5 mmol) and the resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent removed in vacuo to give a yellow oil. Column chromatography using a methanol / dichloromethane gradient (0: 100 to 35:65) gave the title compound (0.8 g, 41% yield) as a white glassy solid:

Mass spectrum (API-TIS) m / z 596 (MNH ₄ ⁺ ).

0℃でアミノアセトアルデヒドジメチルアセタール(2.18 mL, 2.13 g, 20.2 mmol)のEtOAc (25 mL)溶液に、HClのエーテル溶液(13 mL, エーテル中2 N溶液)を滴下した。混合物を0℃で5分間撹拌した。この溶液に、4-クロロ-6-アミノベンゼン-1,3-ジスルホンアミド(Aldrich, 5.8 g, 20.3 mmol)のジエチレングリコールジメチルエーテル(30 mL)液を加えた。次いで、反応混合物を60〜90℃で1時間加熱した。溶媒をデカントし、固形物を水に溶解した。Na₂CO₃水溶液(10%)を加えてpH 7〜8に調整し、EtOAcで抽出し、Na₂SO₄で乾燥し、ろ過し、溶媒を蒸発させた。粗材料をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:EtOAc:MeOH (1:1:0.2〜1:1:1)で溶出させて、表題の化合物(3 g, 収率53%)を白色の固形物として得た: mp 157-160℃。

質量スペクトル(API-TIS) m/z 325 (M-H)、327 (MH⁺); C₈H₁₁ClN₄O₄S₂₀に対し算出された分析値: C, 30.06; H, 3.54; N, 16.70。実測値: C, 30.26; H, 3.40; N, 16.38。 Example 57: Acetamide, N-[[7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] Methyl] -2- [bis [2- (nitrooxy) ethyl] amino]-
57a. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- (aminomethyl) -6-chloro-3,4-dihydro-, 1,1-dioxide

To a solution of aminoacetaldehyde dimethyl acetal (2.18 mL, 2.13 g, 20.2 mmol) in EtOAc (25 mL) at 0 ° C. was added dropwise an ether solution of HCl (13 mL, 2 N solution in ether). The mixture was stirred at 0 ° C. for 5 minutes. To this solution was added 4-chloro-6-aminobenzene-1,3-disulfonamide (Aldrich, 5.8 g, 20.3 mmol) in diethylene glycol dimethyl ether (30 mL). The reaction mixture was then heated at 60-90 ° C. for 1 hour. The solvent was decanted and the solid was dissolved in water. It was adjusted to pH 7 to 8 by addition of aqueous Na ₂ CO ₃ (10%), extracted with EtOAc, dried over Na ₂ SO _4, filtered and the solvent was evaporated. The crude material was chromatographed on silica gel _{CH 2 Cl 2: EtOAc: MeOH} (1: 1: 0.2~1: 1: 1) in eluting, the title compound (3 g, 53% yield) white Obtained as a solid of: mp 157-160 ° C.

Mass spectrum (API-TIS) m / z 325 (MH), 327 (MH ⁺ ); calculated for C ₈ H ₁₁ ClN ₄ O ₄ S ₂₀ : C, 30.06; H, 3.54; N, 16.70 . Found: C, 30.26; H, 3.40; N, 16.38.

実施例57aの生成物(1.3 g, 3.98 mmol)の無水ジオキサン(2 mL)懸濁液に、塩化ブロモアセチル(0.93 g, 0.49 mL, 6.0 mmol)を滴下した。反応混合物を60〜90℃で45分間加熱した。溶媒を蒸発させ、CH₂Cl₂で希釈した。固形物をろ過し、CH₂Cl₂:EtOAcから再結晶して、表題の化合物(1.5 g, 84%)をオフホワイト色の固形物として得た: mp 204-207℃; 質量スペクトル(API-TIS) m/z 445/447 (M-H)、447/449 (MH⁺)。 57b. Acetamide, N-[[7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] methyl] -2-Bromo-

Bromoacetyl chloride (0.93 g, 0.49 mL, 6.0 mmol) was added dropwise to a suspension of the product of Example 57a (1.3 g, 3.98 mmol) in anhydrous dioxane (2 mL). The reaction mixture was heated at 60-90 ° C. for 45 minutes. The solvent was evaporated and diluted with CH ₂ Cl ₂ . The solid was filtered and recrystallized from CH ₂ Cl ₂ : EtOAc to give the title compound (1.5 g, 84%) as an off-white solid: mp 204-207 ° C .; mass spectrum (API- TIS) m / z 445/447 (MH), 447/449 (MH ⁺ ).

実施例57bの生成物(0.5 g, 1.12 mmol)、実施例49aの生成物(0.87 g, 3.4 mmol)およびNaHCO₃ (0.31 g, 3.7 mmol)のDMF (6 mL)混合物を室温で28時間撹拌した。溶媒の蒸発後、残留物を最少量のMeOHに溶解し、固形物をろ過し、ろ液をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:MeOH (1:0.01〜1:0.2)で溶出させて、表題の化合物(0.2 g, 収率32%)を白色の固形物として得た: mp 118℃ (分解);

質量スペクトル(API-TIS) m/z 562 (MH⁺); C₁₄H₂₀ClN₇O₁₁S₂に対し算出された分析値: C, 29.92; H, 3.59; N, 17.45。実測値: C, 29.65; H, 3.41; N, 17.20。 57c. Acetamide, N-[[7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] methyl] -2- [Bis [2- (nitrooxy) ethyl] amino]-

A mixture of the product of Example 57b (0.5 g, 1.12 mmol), the product of Example 49a (0.87 g, 3.4 mmol) and NaHCO ₃ (0.31 g, 3.7 mmol) in DMF (6 mL) was stirred at room temperature for 28 hours. did. After evaporation of the solvent, the residue was dissolved in a minimum amount of MeOH, the solid was filtered, the filtrate was chromatographed on silica gel CH ₂ Cl _2: MeOH eluted with (1: 0.01 0.2) Gave the title compound (0.2 g, 32% yield) as a white solid: mp 118 ° C. (decomposition);

Mass spectrum (API-TIS) m / z 562 (MH ⁺ ); Calculated for C ₁₄ H ₂₀ ClN ₇ O ₁₁ S ₂ : C, 29.92; H, 3.59; N, 17.45. Found: C, 29.65; H, 3.41; N, 17.20.

表題の化合物を実施例35aの手順に従うことにより、6-ブロモ-1-ヘキサノール(8.15 g, 45 mmol)から液体(10 g, 収率98%)として調製した。

Example 58: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [6- (nitrooxy) hexyl]-, 1,1-dioxide
58a. 1-Hexanol, 6-Bromo-, Nitrate

The title compound was prepared as a liquid (10 g, 98% yield) from 6-bromo-1-hexanol (8.15 g, 45 mmol) by following the procedure of Example 35a.

表題の化合物を実施例35bの手順に従うことにより、ヒドロクロロチアジド(13.1 g, 44 mmol)、実施例58aの生成物(10 g, 44 mmol)、および炭酸セシウム(7.17 g, 22 mmol)から白色の多角柱状結晶(12.3 g, 収率63%)として合成した: mp 158-160℃;

質量スペクトル(API-TIS) m/z 443.2および445.3 (それぞれ³⁵Clおよび³⁷ClのMH⁺); C₁₃H₁₉ClN₄O₇S₂に対し算出された分析値: C, 35.25; H, 4.32; N, 12.65; 実測値: C, 33.45; H, 4.26; N, 12.41。 58b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [6- (nitrooxy) hexyl]-, 1,1-dioxide

By following the procedure of Example 35b for the title compound, hydrochlorothiazide (13.1 g, 44 mmol), the product of Example 58a (10 g, 44 mmol) and cesium carbonate (7.17 g, 22 mmol) Synthesized as columnar crystals (12.3 g, 63% yield): mp 158-160 ° C;

Mass spectrum (API-TIS) m / z 443.2 and 445.3 (MH ⁺ of ³⁵ Cl and ³⁷ Cl respectively); calculated values for C ₁₃ H ₁₉ ClN ₄ O ₇ S ₂ : C, 35.25; H, 4.32 N, 12.65; Found: C, 33.45; H, 4.26; N, 12.41.

ヒドロクロロチアジド(3.15 g, 10.6 mmol)のDMF (30 mL)撹拌溶液に、炭酸カリウム(0.732 g, 5.3 mmol)、および3-ブロモ-1-プロパノール(1.47 g, 10.6 mmol)を加えた。室温で22時間撹拌した後に、混合物を水に注ぎ入れ、EtOAcで抽出した。有機層をNaCl水溶液で洗浄し、Na₂SO₄のパッドを通してろ過し、濃縮した。クロマトグラフィー(シリカゲル; EtOAc、その後THF)とそれに続くEtOAc:CH₂Cl₂ (1:1)からの再結晶により、表題の化合物(1.02 g, 収率27%)を白色の多角柱状結晶として得た: mp 160℃;

質量スペクトル(API-TIS) m/z 356.2および358.1 (それぞれ³⁵Clおよび³⁷ClのMH⁺)。 Example 59: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- (3-hydroxypropyl)-, 1,1-dioxide

To a stirred solution of hydrochlorothiazide (3.15 g, 10.6 mmol) in DMF (30 mL) was added potassium carbonate (0.732 g, 5.3 mmol) and 3-bromo-1-propanol (1.47 g, 10.6 mmol). After stirring at room temperature for 22 hours, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with aqueous NaCl, filtered through a pad of Na ₂ SO ₄ and concentrated. Chromatography (silica gel; EtOAc, then THF) followed by recrystallization from EtOAc: CH ₂ Cl ₂ (1: 1) gave the title compound (1.02 g, 27% yield) as white polygonal crystals. T: mp 160 ℃;

Mass spectrum (API-TIS) m / z 356.2 and 358.1 (MH ^{+ of 35} Cl and ³⁷ Cl, respectively).

ヒドロクロロチアジド(3.65 g, 12.3 mmol)のDMF (30 mL)撹拌溶液に、炭酸セシウム(2.00 g, 6.15 mmol)、および5-ブロモ-1-ペンタノール(2.05 g, 12.3 mmol)を加えた。室温で66時間撹拌した後に、混合物を水に注ぎ入れ、EtOAcで抽出した。有機層をNaCl水溶液で洗浄し、Na₂SO₄のパッドを通してろ過し、濃縮した。クロマトグラフィー(シリカゲル; EtOAc、その後THF)とそれに続くEtOAc:CH₂Cl₂:ヘキサン(1:1:1)からの再結晶により、表題の化合物(2.21 g, 収率47%)を白色の固形物として得た: mp 177-179℃;

質量スペクトル(API-TIS) m/z 384.3および386.2 (それぞれ³⁵Clおよび³⁷ClのMH⁺)。 Example 60: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- (5-hydroxypentyl)-, 1,1-dioxide

To a stirred solution of hydrochlorothiazide (3.65 g, 12.3 mmol) in DMF (30 mL) was added cesium carbonate (2.00 g, 6.15 mmol) and 5-bromo-1-pentanol (2.05 g, 12.3 mmol). After stirring at room temperature for 66 hours, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with aqueous NaCl, filtered through a pad of Na ₂ SO ₄ and concentrated. Chromatography (silica gel; EtOAc, then THF) followed by recrystallization from EtOAc: CH ₂ Cl ₂ : hexanes (1: 1: 1) gave the title compound (2.21 g, 47% yield) as a white solid Obtained as: mp 177-179 ℃;

Mass spectrum (API-TIS) m / z 384.3 and 386.2 (MH ^{+ of 35} Cl and ³⁷ Cl, respectively).

2-(4-ブロモブチル)-5,5-ジメチル-1,3-ジオキサン(34.8 g, 150 mmol, 米国特許第4,847,391号中の手順に従ってネオペンチルグリコールおよび3,4-ジヒドロ-2H-ピランの反応により調製)を無水アセトニトリル中にて硝酸銀(35.5 g, 210 mmol)で処理した。得られた混合物を2時間還流し、室温に冷却し、沈殿物をろ過により除去した。ろ液を減圧で蒸発させ、次に酢酸エチル(2×)で抽出した。合わせた抽出液を蒸留水(2×50 mL)、塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、溶媒を減圧で蒸発させて、表題の化合物(32.5 g)をほぼ定量的な収率の無色粘稠な油状物として得た。 Example 61: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- [4- (nitrooxy) butyl] -6- (trifluoromethyl)-, 1, 1-dioxide
61a. 1,3-Dioxane-2-butanol, 5,5-dimethyl-, nitrate

Reaction of neopentyl glycol and 3,4-dihydro-2H-pyran according to the procedure in 2- (4-bromobutyl) -5,5-dimethyl-1,3-dioxane (34.8 g, 150 mmol, U.S. Pat.No. 4,847,391) Was prepared with silver nitrate (35.5 g, 210 mmol) in anhydrous acetonitrile. The resulting mixture was refluxed for 2 hours, cooled to room temperature, and the precipitate was removed by filtration. The filtrate was evaporated under reduced pressure and then extracted with ethyl acetate (2 ×). The combined extracts were distilled water (2 × 50 mL), washed with brine, dried over Na ₂ SO _4, filtered and the solvent was evaporated under reduced pressure to give the title compound (32.5 g) nearly quantitative Obtained as a colorless viscous oil in yield.

実施例61aの粗生成物(2.36 g, 11 mmol)および2-アミノ-6- (トリフルオロメチル)-1,3-ベンゼンジスルホンアミド(1.595 g, 5 mmol)をジオキサン(75 mL)および濃塩酸(1 mL)の中で一緒に混合した。反応混合物を一晩還流し、室温に冷却し、飽和塩水で洗浄した。有機層を分離し、溶媒を減圧で蒸発させた。得られた残留物を水で処理し、旋回し、水をデカントし、捨てた。次に、残留物を酢酸エチル(2×)で抽出した。合わせた抽出液を炭酸ナトリウム飽和水溶液、水、塩水で洗浄し、硫酸ナトリウムで乾燥し、ろ過し、ろ液を真空で濃縮して粗生成物を得た。シリカゲルのカラムクロマトグラフィーにより4%メタノールのジクロロメタン液で溶出させ精製して、油状物(1 g)を得、これを40%酢酸エチルのヘキサン液から結晶化して、表題の化合物(850 mg, 収率38%)を白色の固形物として得た: mp 171-177℃;

質量スペクトル(API-TIS) m/z 449 (MH)⁺、466 (MNH₄)⁺。 61b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- [4- (nitrooxy) butyl] -6- (trifluoromethyl)-, 1,1- Dioxide

The crude product of Example 61a (2.36 g, 11 mmol) and 2-amino-6- (trifluoromethyl) -1,3-benzenedisulfonamide (1.595 g, 5 mmol) were mixed with dioxane (75 mL) and concentrated hydrochloric acid. Mixed together in (1 mL). The reaction mixture was refluxed overnight, cooled to room temperature and washed with saturated brine. The organic layer was separated and the solvent was evaporated under reduced pressure. The resulting residue was treated with water, swirled, water decanted and discarded. The residue was then extracted with ethyl acetate (2x). The combined extracts were washed with a saturated aqueous sodium carbonate solution, water and brine, dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give a crude product. Purification by column chromatography on silica gel eluting with 4% methanol in dichloromethane gave an oil (1 g) which was crystallized from 40% ethyl acetate in hexane to give the title compound (850 mg, yield). Yield 38%) as a white solid: mp 171-177 ° C;

Mass spectrum (API-TIS) m / z 449 (MH) ⁺ , 466 (MNH ₄ ) ⁺ .

表題の化合物は実施例26の手順に従うことによって、5-ヒドロキシ-1-ペンタナール(2.04 g, 20 mmol)および2-アミノ-6-(トリフルオロメチル)-1,3-ベンゼンジスルホンアミド(2.87 g, 10 mmol)の反応により調製される。 Example 62. 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- (4-hydroxybutyl) -6- (trifluoromethyl)-, 1,1- Dioxide

The title compound was prepared according to the procedure of Example 26 by 5-hydroxy-1-pentanal (2.04 g, 20 mmol) and 2-amino-6- (trifluoromethyl) -1,3-benzenedisulfonamide (2.87 g , 10 mmol).

表題の化合物を実施例57aの手順に従うことにより、4-クロロ-6-アミノベンゼン-1,3-ジスルホンアミド(Aldrich)から白色の固形物(3.4 g, 49%)として調製した: mp 145-147℃;

質量スペクトル(API-TIS) m/z 339 (M-H)、341 (MH⁺); C₉H₁₃ClN₄O₄S₂に対し算出された分析値: C, 31.72; H, 3.84; N, 16.44; 実測値: C, 31.64; H, 3.85; N, 16.19。 Example 63: Acetamide, N-[[7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] Methyl] -2- [bis [2- (nitrooxy) ethyl] amino] -N-methyl-
63a. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[(methylamino) methyl]-, 1,1-dioxide

The title compound was prepared as a white solid (3.4 g, 49%) from 4-chloro-6-aminobenzene-1,3-disulfonamide (Aldrich) by following the procedure in Example 57a: mp 145- 147 ° C;

Mass spectrum (API-TIS) m / z 339 (MH), 341 (MH ⁺ ); calculated for C ₉ H ₁₃ ClN ₄ O ₄ S ₂ : C, 31.72; H, 3.84; N, 16.44 Found: C, 31.64; H, 3.85; N, 16.19.

表題の化合物を実施例57bの手順に従うことにより、実施例63aの生成物から白色の固形物(1.3 g, 96%)として調製した: mp 150-152℃; 質量スペクトル(API-TIS) m/z 461/463 (MH⁺)。 63b. N-{[7- (Aminosulfonyl) -6-chloro-1,1-dioxide-3,4-dihydro-2H-1,2,4-benzothiadiazin-3-yl] methyl} -2 -Bromo-N-methylacetamide

The title compound was prepared as a white solid (1.3 g, 96%) from the product of Example 63a by following the procedure of Example 57b: mp 150-152 ° C .; mass spectrum (API-TIS) m / z 461/463 (MH ⁺ ).

表題の化合物を実施例57cの手順に従うことにより、実施例63bの生成物からオフホワイト色の固形物(0.15 g, 24%)として調製した: mp 183-185℃ (分解);

質量スペクトル(API-TIS) m/z 574 (M-H)、576 (MH⁺); C₁₅H₂₂ClN₇O₁₁S₂・0.3モルEtOAcに対し算出された分析値: C, 32.30; H, 4.05; N, 16.28; 実測値: C, 32.00; H, 3.66; N, 15.89。 63c. Acetamide, N-[[7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] methyl] -2- [Bis [2- (nitrooxy) ethyl] amino] -N-methyl-

The title compound was prepared as an off-white solid (0.15 g, 24%) from the product of Example 63b by following the procedure of Example 57c: mp 183-185 ° C. (decomposition);

Mass spectrum (API-TIS) m / z 574 (MH), 576 (MH ⁺ ); Analytical values calculated for C ₁₅ H ₂₂ ClN ₇ O ₁₁ S ₂ 0.3 mol EtOAc: C, 32.30; H, 4.05 N, 16.28; Found: C, 32.00; H, 3.66; N, 15.89.

DMF (1 mL)およびアセトニトリル(20 mL)の混合液中の実施例5aの生成物(0.354 g, 2 mmol)、N-(3-ジメチルアミノプロピル)-N'-エチルカルボジイミド塩酸塩(0.383 g, 2 mmol)、1-ヒドロキシベンゾトリアゾール水和物(0.270 g, 2 mmol)、および実施例12bの生成物(0.780 g, 1.78 mmol)の撹拌混合物に、トリエチルアミン(1.40 mL, 10 mmol)を加えた。添加後、混合物を室温で1時間撹拌した。混合物を濃縮して揮発性物質を除去し、EtOAcで処理し、水、NaHCO₃水溶液、およびNaCl水溶液で洗浄した。有機層をNa₂SO₄で乾燥し、ろ過し、濃縮して固形物を得た。粗生成物のクロマトグラフィー(シリカゲル、負荷の場合THF、溶出の場合EtOAc)とそれに続くEtOAc:ヘキサン(5:1)からの再結晶により、表題の化合物(0.460 g, 収率46%)を白色の多角柱状結晶として得た: mp 162-165℃ (分解);

質量スペクトル(API-TIS) m/z 560.1 (MH⁺)。 Example 64: Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[6 (nitrooxy) -1-oxohexyl]- 6- (Trifluoromethyl)-, 1,1-dioxide

The product of Example 5a (0.354 g, 2 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (0.383 g) in a mixture of DMF (1 mL) and acetonitrile (20 mL). Triethylamine (1.40 mL, 10 mmol) was added to a stirred mixture of 1-hydroxybenzotriazole hydrate (0.270 g, 2 mmol) and the product of Example 12b (0.780 g, 1.78 mmol). It was. After the addition, the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to remove volatiles, treated with EtOAc, and washed with water, aqueous NaHCO ₃ , and aqueous NaCl. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give a solid. Chromatography of the crude product (silica gel, THF for loading, EtOAc for elution) followed by recrystallization from EtOAc: hexane (5: 1) gave the title compound (0.460 g, 46% yield) in white Obtained as a polygonal column of crystal: mp 162-165 ℃ (decomposition);

Mass spectrum (API-TIS) m / z 560.1 (MH ⁺ ).

3,5-ビス(ヒドロキシメチル)安息香酸(1.7 g, 9.3 mmol, Tetrahedron 49: 8761, 1993に記載のように調製)のTHF (100 mL)溶液を発煙硝酸(2.2 mL, 47.1 mol)の無水酢酸(25 mL)のあらかじめ混合した溶液で処理し、室温で1時間撹拌した。反応混合物を減圧下で蒸発乾固し、生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(3:2, R_f=0.2)で溶出させて精製し、表題の化合物(1.28 g, 収率51%)を白色の固形物として得た: mp 39-41℃;

質量スペクトル(API-TIS) m/z 271 (M-H)^-。 Example 65: (5-{[{[7- (aminosulfonyl) -6-chloro-1,1-dioxide-3,4-dihydro-2H-1,2,4-benzothiadiazin-3-yl ] Methyl} (methyl) amino] carbonyl} -1,3-phenylene) bis (methylene) dinitrate
65a. 3,5-Bis [(nitrooxy) methyl] benzoic acid

A solution of 3,5-bis (hydroxymethyl) benzoic acid (1.7 g, 9.3 mmol, prepared as described in Tetrahedron 49: 8761, 1993) in THF (100 mL) was added anhydrous fuming nitric acid (2.2 mL, 47.1 mol). Treated with a premixed solution of acetic acid (25 mL) and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure and the product was purified by silica gel column chromatography eluting with EtOAc / hexane (3: 2, R _f = 0.2) to give the title compound (1.28 g, 51% yield). ) Was obtained as a white solid: mp 39-41 ° C .;

Mass spectrum (API-TIS) m / z 271 (MH) ^- .

塩化オキサリル(0.4 mL, 4.4 mmol)を実施例65aの生成物(0.9 g, 3.4 mmol)のCH₂Cl₂ (50 mL)およびDMF (50 μL)溶液に加え、室温で1時間撹拌した。反応混合物を蒸発乾固し、真空下で乾燥して、表題の化合物を淡色の油状物として得た。生成物を精製せずに次の段階で用いた。

65b. [5- (Chlorocarbonyl) -1,3-phenylene] bis (methylene) dinitrate

Oxalyl chloride (0.4 mL, 4.4 mmol) was added to a solution of the product of Example 65a (0.9 g, 3.4 mmol) in CH ₂ Cl ₂ (50 mL) and DMF (50 μL) and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness and dried under vacuum to give the title compound as a pale oil. The product was used in the next step without purification.

(メチルアミノ)アセトアルデヒドジメチルアセタール(0.5 mL, 3.9 mmol)およびNEt₃ (0.5 mL, 3.6 mmol)を実施例65bの粗生成物のCH₂Cl₂ (50 mL)に加え、室温で5時間撹拌した。反応物をCH₂Cl₂ (100 mL)と3 N HCl (50 mL)との間で分配した。有機抽出液を水、塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮し、真空下で乾燥した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(3:2でR_f=0.23)で溶出させて分離し、表題の化合物をZ、E異性体の混合物(1.1 g, 収率84%)として油状物として得た: 質量スペクトル(API-TIS) m/z 374 (MH)⁺。 65c. (5-{[(2,2-Dimethoxyethyl) (methyl) amino] carbonyl} -1,3-phenylene) bis (methylene) dinitrate

(Methylamino) acetaldehyde dimethyl acetal (0.5 mL, 3.9 mmol) and NEt ₃ (0.5 mL, 3.6 mmol) were added to the crude product CH ₂ Cl ₂ (50 mL) of Example 65b and stirred at room temperature for 5 hours. . The reaction was partitioned between CH ₂ Cl ₂ (100 mL) and 3 N HCl (50 mL). The organic extract was washed with water, brine, dried over Na ₂ SO ₄ , filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with EtOAc / hexane (3: 2 R _f = 0.23) to give the title compound as a mixture of Z, E isomers (1.1 g, 84% yield) as an oil Obtained as: mass spectrum (API-TIS) m / z 374 (MH) ⁺ .

4-アミノ-6-クロロ-1,3-ベンゼンジスルホンアミド(0.8 g, 2.8 mmol)、実施例65cの生成物(1.1 g, 2.8 mmol)および濃HCl (0.25 mL, 3.0 mmol)のジオキサン(30 mL)混合物を90℃に1.5時間加熱した。反応混合物を減圧下で蒸発乾固した。得られた材料をEtOAc (100 mL×2)と3 N HCl (50 mL)との間で分配した。有機抽出液を水、塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮し、真空下で乾燥した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(5:1でR_f=0.25)で溶出させて精製し、表題の化合物をZ、E異性体の混合物として、白色の固形物(0.7 g, 収率41%)として得た: mp 137℃ (分解);

質量スペクトル(API-TIS) m/z 595 (MH)⁺。C₁₈H₁₉ClN₆O₁₁S₂に対し算出された分析値: C, 36.34; H, 3.22; N, 14.13; 実測値: C, 36.06; H, 3.00; N, 13.83。 65d. (5-{[{[7- (Aminosulfonyl) -6-chloro-1,1-dioxide-3,4-dihydro-2H-1,2,4-benzothiadiazin-3-yl] methyl } (Methyl) amino] carbonyl} -1,3-phenylene) bis (methylene) dinitrate

4-Amino-6-chloro-1,3-benzenedisulfonamide (0.8 g, 2.8 mmol), the product of Example 65c (1.1 g, 2.8 mmol) and concentrated HCl (0.25 mL, 3.0 mmol) in dioxane (30 mL) The mixture was heated to 90 ° C. for 1.5 h. The reaction mixture was evaporated to dryness under reduced pressure. The resulting material was partitioned between EtOAc (100 mL × 2) and 3 N HCl (50 mL). The organic extract was washed with water, brine, dried over Na ₂ SO ₄ , filtered, concentrated and dried under vacuum. The product was purified by silica gel column chromatography eluting with EtOAc / hexane (5: 1, R _f = 0.25) to give the title compound as a mixture of Z, E isomers as a white solid (0.7 g, yield). Rate 41%) obtained as: mp 137 ℃ (decomposition);

Mass spectrum (API-TIS) m / z 595 (MH) ⁺ . Calculated for C ₁₈ H ₁₉ ClN ₆ O ₁₁ S ₂ : C, 36.34; H, 3.22; N, 14.13; Found: C, 36.06; H, 3.00; N, 13.83.

ヒドロクロロチアジド(6.25 g, 21 mmol)のDMF (60 mL)撹拌溶液に、炭酸セシウム(3.32 g, 10.2 mmol)、および6-ブロモ-1-ヘキサノール(3.70 g, 20.4 mmol)を加えた。室温で25時間撹拌した後に、混合物を水に注ぎ入れ、EtOAcで抽出した。有機層をNaCl水溶液で洗浄し、Na₂SO₄のパッドを通してろ過し、濃縮した。クロマトグラフィー(シリカゲル; EtOAc、その後THF)とそれに続くEtOAc:CH₂Cl₂ (1:3)からの再結晶により、表題の化合物(3.02 g, 収率37%)を白色の固形物として得た: mp 176-179℃;

質量スペクトル(API-TIS) m/z 398.2および400.3 (それぞれ³⁵Clおよび³⁷ClのMH⁺)。 Example 66: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- (6-hydroxyhexyl)-, 1,1-dioxide

To a stirred solution of hydrochlorothiazide (6.25 g, 21 mmol) in DMF (60 mL) was added cesium carbonate (3.32 g, 10.2 mmol) and 6-bromo-1-hexanol (3.70 g, 20.4 mmol). After stirring at room temperature for 25 hours, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with aqueous NaCl, filtered through a pad of Na ₂ SO ₄ and concentrated. Chromatography (silica gel; EtOAc, then THF) followed by recrystallization from EtOAc: CH ₂ Cl ₂ (1: 3) gave the title compound (3.02 g, 37% yield) as a white solid. : mp 176-179 ° C;

Mass spectrum (API-TIS) m / z 398.2 and 400.3 (MH ^{+ of 35} Cl and ³⁷ Cl, respectively).

室温でトランス-1,4-ジブロモ-2-ブテン(ACROS, 7 g, 32.7 mmol)のCH₃CN (40 mL)撹拌溶液に、硝酸銀(5.6 g, 32.7 mmol)を加えた。反応混合物を室温で16時間撹拌した。ろ過および溶媒の蒸発後の残留物をシリカゲルのクロマトグラフィーにより分離しEtOAc:ヘキサン(0.1:1)で溶出させて、表題の化合物(3 g, 収率47%)を油状物として得た。

Example 67: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2-[(2E) -4- (nitrooxy) -2-butenyl]- 1,1-dioxide
67a. 2-Buten-1-ol, 4-bromo-, nitrate, (2E)-

Silver nitrate (5.6 g, 32.7 mmol) was added to a stirred solution of trans-1,4-dibromo-2-butene (ACROS, 7 g, 32.7 mmol) in CH ₃ CN (40 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The residue after filtration and evaporation of the solvent was separated by chromatography on silica gel and eluted with EtOAc: hexane (0.1: 1) to give the title compound (3 g, 47% yield) as an oil.

実施例67aの生成物(0.78 g, 4.0 mmol)、ヒドロクロロチアジド(ONBIO Inc., 1 g, 3.4 mmol)およびK₂CO₃ (0.46 g, 3.3 mmol)の無水DMF (5 mL)混合物を室温で3時間撹拌した。次いで、反応混合物をEtOAcで希釈し、ろ過し、蒸発させた。残留物をEtOAcに再溶解し、0.1 N氷冷HClで洗浄し、Na₂SO₄で乾燥した。ろ過および溶媒の蒸発後の残留物をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:MeOH (1:0.1)で溶出させて、表題の化合物(0.39 g, 収率28%)を白色の固形物として得た: mp 160-162℃ (分解);

質量スペクトル(API-TIS) m/z 411 (M-H)、413 (MH⁺)、430 (MNH₄ ⁺)。C₁₁H₁₃ClN₄O₇S₂・1/4モルCH₂Cl₂に対し算出された分析値: C, 31.13; H, 3.13; N, 12.90。実測値: C, 31.51; H, 2.93; N, 12.56。 67b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2-[(2E) -4- (nitrooxy) -2-butenyl]-, 1 , 1-dioxide

A mixture of the product of Example 67a (0.78 g, 4.0 mmol), hydrochlorothiazide (ONBIO Inc., 1 g, 3.4 mmol) and K ₂ CO ₃ (0.46 g, 3.3 mmol) in anhydrous DMF (5 mL) at room temperature Stir for hours. The reaction mixture was then diluted with EtOAc, filtered and evaporated. The residue was redissolved in EtOAc, washed with 0.1 N ice-cold HCl and dried over Na ₂ SO ₄ . The residue after filtration and evaporation of the solvent was separated by chromatography on silica gel eluting with CH ₂ Cl ₂ : MeOH (1: 0.1) to give the title compound (0.39 g, 28% yield) as a white solid Obtained as: mp 160-162 ℃ (decomposition);

Mass spectrum (API-TIS) m / z 411 (MH), 413 (MH ⁺ ), 430 (MNH ₄ ⁺ ). Analytical values calculated for C ₁₁ H ₁₃ ClN ₄ O ₇ S ₂ · 1/4 mol CH ₂ Cl ₂ : C, 31.13; H, 3.13; N, 12.90. Found: C, 31.51; H, 2.93; N, 12.56.

0℃でLiAlH₄ (95 mL, THF中1 M, 95 mmol)の溶液に、5-ヒドロキシイソフタル酸ジメチルエステル(Aldrich, 5 g, 24 mmol)のTHF (100 mL)溶液を滴下した。反応混合物を室温で3時間、その後70℃で1.5時間撹拌した。反応混合物を0℃にて10% H₂SO₄水溶液で注意深く酸性化した。固形物をろ過し、CH₂Cl₂:MeOH (1:1)の混合物で抽出した。合わせた有機抽出液をNa₂SO₄で乾燥し、ろ過し、蒸発させた。粗生成物をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:MeOH (9:1〜7:3)で溶出させて、表題の化合物(3.6 g, 収率98%)を白色の固形物として得た: mp 70-72℃。

質量スペクトル(API-TIS) m/z 155 (MH⁺)、153 (M-H)、172 (MNH₄ ⁺)。 Example 68: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 2-[[3- (4-bromobutoxy) -5-[(nitrooxy) methyl] phenyl] methyl] -6- Chloro-3,4-dihydro-, 1,1-dioxide
68a. 1,3-Benzenedimethanol, 5-hydroxy-

To a solution of LiAlH ₄ (95 mL, 1 M in THF, 95 mmol) at 0 ° C. was added dropwise a solution of 5-hydroxyisophthalic acid dimethyl ester (Aldrich, 5 g, 24 mmol) in THF (100 mL). The reaction mixture was stirred at room temperature for 3 hours and then at 70 ° C. for 1.5 hours. The reaction mixture was carefully acidified with 10% aqueous H ₂ SO ₄ at 0 ° C. The solid was filtered and extracted with a mixture of CH ₂ Cl ₂ : MeOH (1: 1). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was separated by chromatography on silica gel and eluted with CH ₂ Cl ₂ : MeOH (9: 1 to 7: 3) to give the title compound (3.6 g, 98% yield) as a white solid. T: MP 70-72 ℃.

Mass spectrum (API-TIS) m / z 155 (MH ⁺ ), 153 (MH), 172 (MNH ₄ ⁺ ).

実施例68aの生成物(2 g, 13 mmol)、ジブロモブタン(11.5 mL, 20.6 g, 95 mmol)およびK₂CO₃ (1.9 g, 13.8 mmol)の無水DMF (15 mL)混合物を室温で2日間撹拌した。ろ過および蒸発後の残留物をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:MeOH (9:1〜7:3〜1:1)で溶出させて、表題の化合物(1.6 g, 収率43%)をオフホワイト色の固形物として得た: mp 46-48℃。

質量スペクトル(API-TIS) m/z 289/291 (MH⁺)、306/308 (MNH₄ ⁺)、271/273 (M-OH)。
C₁₂H₁₇BrO₃に対し算出された分析値: C, 49.84; H, 5.93。実測値: C, 50.09; H, 5.97。 68b. 1,3-Benzenedimethanol, 5- (4-bromobutoxy)-

Mix the product of Example 68a (2 g, 13 mmol), dibromobutane (11.5 mL, 20.6 g, 95 mmol) and K ₂ CO ₃ (1.9 g, 13.8 mmol) in anhydrous DMF (15 mL) at room temperature. Stir for days. The residue after filtration and evaporation was separated by chromatography on silica gel and eluted with CH ₂ Cl ₂ : MeOH (9: 1 to 7: 3 to 1: 1) to give the title compound (1.6 g, 43% yield). ) Was obtained as an off-white solid: mp 46-48 ° C.

Mass spectrum (API-TIS) m / z 289/291 (MH ⁺ ), 306/308 (MNH ₄ ⁺ ), 271/273 (M-OH).
Analytical value calculated for C ₁₂ H ₁₇ BrO ₃ : C, 49.84; H, 5.93. Found: C, 50.09; H, 5.97.

発煙HNO₃ (1.2 g, 0.8 mL, 19 mmol)を0℃でAc₂O (3 g, 2.8 mL, 29.7 mmol)に滴下した。反応混合物を0℃で1時間撹拌した。次いで、実施例68bの生成物(1.1 g, 3.8 mmol)のEtOAc (15 mL)溶液を15分かけて滴下した。得られた混合物を0℃で1時間撹拌し、EtOAcで希釈し、10% NaHCO₃の氷冷溶液、水で洗浄し、Na₂SO₄で乾燥した。ろ過および溶媒の蒸発後の残留物をシリカゲルのクロマトグラフィーにより分離しヘキサン:EtOAc (9:1〜7:3)で溶出させて、表題の化合物(0.9 g, 収率63%)を半固形物として得た。

質量スペクトル(API-TIS) m/z 396 (MNH₄ ⁺)。 68c. 1,3-Benzenedimethanol, 5- (4-bromobutoxy)-, dinitrate

Fuming HNO ₃ (1.2 g, 0.8 mL, 19 mmol) was added dropwise to Ac ₂ O (3 g, 2.8 mL, 29.7 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hour. A solution of the product of Example 68b (1.1 g, 3.8 mmol) in EtOAc (15 mL) was then added dropwise over 15 minutes. The resulting mixture was stirred at 0 ° C. for 1 h, diluted with EtOAc, washed with an ice-cold solution of 10% NaHCO ₃ , water and dried over Na ₂ SO ₄ . The residue after filtration and evaporation of the solvent was separated by chromatography on silica gel eluting with hexane: EtOAc (9: 1 to 7: 3) to give the title compound (0.9 g, 63% yield) as a semi-solid Got as.

Mass spectrum (API-TIS) m / z 396 (MNH ₄ ⁺ ).

実施例68cの生成物(0.82 g, 2.2 mmol)、ヒドロクロロチアジド(ONBIO Inc., 0.77 g, 2.6 mmol)およびK₂CO₃ (0.29 g, 2.1 mmol)の無水DMF (5 mL)混合物を0℃で30分間撹拌した。次いで、得られた混合物を室温に徐々に加温し、室温で3時間撹拌した。次に、反応混合物をEtOAcで希釈し、ろ過し、蒸発させた。残留物をEtOAcに再溶解し、0.1 N氷冷HCl、水で洗浄し、Na₂SO₄で乾燥した。粗生成物をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:EtOAc:MeOH (1:1:0.1)で溶出させて、表題の化合物(0.4 g, 収率30%)を白色の固形物として得た: mp 80℃。

質量スペクトル(API-TIS) m/z 613 (MH⁺)。C₁₉H₂₂BrClN₄O₈S₂に対し算出された分析値: C, 37.17; H, 3.61; N, 9.13。実測値: C, 37.32; H, 3.42; N, 8.88。 68d. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[[3- (4-Bromobutoxy) -5 [(nitrooxy) methyl] phenyl] methyl] -6-chloro-3 , 4-Dihydro-, 1,1-dioxide

A mixture of the product of Example 68c (0.82 g, 2.2 mmol), hydrochlorothiazide (ONBIO Inc., 0.77 g, 2.6 mmol) and K ₂ CO ₃ (0.29 g, 2.1 mmol) in anhydrous DMF (5 mL) at 0 ° C. Stir for 30 minutes. The resulting mixture was then gradually warmed to room temperature and stirred at room temperature for 3 hours. The reaction mixture was then diluted with EtOAc, filtered and evaporated. The residue was redissolved in EtOAc, washed with 0.1 N ice cold HCl, water and dried over Na ₂ SO ₄ . The crude product was separated by chromatography on silica gel and eluted with CH ₂ Cl ₂ : EtOAc: MeOH (1: 1: 0.1) to give the title compound (0.4 g, 30% yield) as a white solid. T: mp 80 ℃.

Mass spectrum (API-TIS) m / z 613 (MH ⁺ ). Analytical values calculated for C ₁₉ H ₂₂ BrClN ₄ O ₈ S ₂ : C, 37.17; H, 3.61; N, 9.13. Found: C, 37.32; H, 3.42; N, 8.88.

実施例68bの生成物(2.74 g, 9.5 mmol)、ヒドロクロロチアジド(ONBIO Inc., 3.38 g, 11.4 mmol)およびK₂CO₃ (1.3 g, 9.4 mmol)の無水DMF (20 mL)混合物を室温で16時間撹拌した。溶媒を蒸発させた。残留物をEtOAcに懸濁し、0.1 N氷冷HCl、水で洗浄し、Na₂SO₄で乾燥した。粗生成物をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:MeOH (9:1〜7:3〜1:1)で溶出させて、表題の化合物(1.2 g, 収率25%)を白色の固形物として得た: mp 78-80℃。

質量スペクトル(API-TIS) m/z 504 (M-H)、506 (MH⁺)、523 (MNa⁺)、488 (M-OH)、470 (M-2×OH)。C₁₉H₂₄ClN₃O₇S₂に対し算出された分析値: C, 45.10; H, 4.78; N, 8.30。実測値: C, 44.90; H, 4.59; N, 8.16。 Example 69: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 2- [4- [3,5-bis [(nitrooxy) methyl] phenoxy] butyl] -6-chloro-3, 4-dihydro-, 1,1-dioxide
69a. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [4- [3,5-bis (hydroxymethyl) phenoxy] butyl] -6-chloro-3,4-dihydro- 1,1-dioxide

A mixture of the product of Example 68b (2.74 g, 9.5 mmol), hydrochlorothiazide (ONBIO Inc., 3.38 g, 11.4 mmol) and K ₂ CO ₃ (1.3 g, 9.4 mmol) in anhydrous DMF (20 mL) at room temperature for 16 Stir for hours. The solvent was evaporated. The residue was suspended in EtOAc, washed with 0.1 N ice cold HCl, water and dried over Na ₂ SO ₄ . The crude product was separated by chromatography on silica gel and eluted with CH ₂ Cl ₂ : MeOH (9: 1 to 7: 3 to 1: 1) to give the title compound (1.2 g, 25% yield) as white Obtained as a solid: mp 78-80 ° C.

Mass spectrum (API-TIS) m / z 504 (MH), 506 (MH ⁺ ), 523 (MNa ⁺ ), 488 (M-OH), 470 (M-2 × OH). Analytical values calculated for C ₁₉ H ₂₄ ClN ₃ O ₇ S ₂ : C, 45.10; H, 4.78; N, 8.30. Found: C, 44.90; H, 4.59; N, 8.16.

-10℃で発煙HNO₃ (0.44 g, 0.29 mL, 6.9 mmol)およびAc₂O (1.1 g, 1 mL, 11.1 mmol)の混合物に、実施例69aの生成物(0.7 g, 1.4 mmol)のTHF (6 mL)溶液を15分間かけて滴下した。反応混合物を-10〜0℃で2時間撹拌し、EtOAcで希釈し、10% NaHCO₃の氷冷溶液、水で洗浄し、Na₂SO₄で乾燥した。ろ過および溶媒の蒸発後の残留物をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:MeOH (9:1〜7:3〜1:1)で溶出させて、表題の化合物(0.9 g, 収率63%)を白色の固形物として得た: mp 65-67℃。

質量スペクトル(API-TIS) m/z 594 (M-H)。C₁₉H₂₂ClN₅O₁₁S₂に対し算出された分析値: C, 38.29; H, 3.72; N, 11.75。実測値: C, 38.58; H, 3.79; N, 11.55。 69b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [4- [3,5-bis [(nitrooxy) methyl] phenoxy] butyl] -6-chloro-3,4- Dihydro-, 1,1-dioxide

To a mixture of fuming HNO ₃ (0.44 g, 0.29 mL, 6.9 mmol) and Ac ₂ O (1.1 g, 1 mL, 11.1 mmol) at −10 ° C., the product of Example 69a (0.7 g, 1.4 mmol) in THF The solution (6 mL) was added dropwise over 15 minutes. The reaction mixture was stirred at −10 to 0 ° C. for 2 hours, diluted with EtOAc, washed with an ice-cold solution of 10% NaHCO ₃ , water and dried over Na ₂ SO ₄ . The residue after filtration and evaporation of the solvent was separated by chromatography on silica gel and eluted with CH ₂ Cl ₂ : MeOH (9: 1 to 7: 3 to 1: 1) to give the title compound (0.9 g, yield) 63%) was obtained as a white solid: mp 65-67 ° C.

Mass spectrum (API-TIS) m / z 594 (MH). Analytical value calculated for C ₁₉ H ₂₂ ClN ₅ O ₁₁ S ₂ : C, 38.29; H, 3.72; N, 11.75. Found: C, 38.58; H, 3.79; N, 11.55.

表題の化合物を実施例68bの手順に従うことにより、無水DMF (8 mL)中にて実施例68aの生成物(2 g, 13 mmol)、ジブロモプロパン(7.9 g, 39.1 mmol)およびK₂CO₃ (1.9 g, 13.8 mmol)から白色の固形物(1.1 g, 31%)として調製した。Mp 70-71℃。

質量スペクトル(API-TIS) m/z 275/277 (MH⁺)、292/294 (MNH₄ ⁺)、257/259 (M-OH)。 Example 70: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 2- [3- [3,5-bis [(nitrooxy) methyl] phenoxy] propyl] -6-chloro-3, 4-dihydro-, 1,1-dioxide
70a. 1,3-Benzenedimethanol, 5- (3-bromopropoxy)-

The title compound was followed by the procedure of Example 68b in anhydrous DMF (8 mL) to give the product of Example 68a (2 g, 13 mmol), dibromopropane (7.9 g, 39.1 mmol) and K ₂ CO ₃ Prepared from (1.9 g, 13.8 mmol) as a white solid (1.1 g, 31%). Mp 70-71 ° C.

Mass spectrum (API-TIS) m / z 275/277 (MH ⁺ ), 292/294 (MNH ₄ ⁺ ), 257/259 (M-OH).

表題の化合物を実施例69aの手順に従うことにより、無水DMF (10 mL)中にて実施例70aの生成物(1.1 g, 4 mmol)、ヒドロクロロチアジド(ONBIO Inc., 1.4 g, 4.7 mmol)およびK₂CO₃ (0.55 g, 4 mmol)から白色の固形物(1.24 g, 63%)として調製した。Mp 155-157℃。

質量スペクトル(API-TIS) m/z 490 (M-H)、509 (MNH₄ ⁺)、474 (M-OH)、457 (M-2×OH)。C₁₈H₂₂ClN₃O₇S₂・1/4モルEtOAcに対し算出された分析値: C, 44.44; H, 4.70; N, 8.18。実測値: C, 44.59; H, 4.49; N, 7.97。 70b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [3- [3,5-bis (hydroxymethyl) phenoxy] propyl] -6-chloro-3,4-dihydro- 1,1-dioxide

The title compound was followed by the procedure of Example 69a in anhydrous DMF (10 mL), the product of Example 70a (1.1 g, 4 mmol), hydrochlorothiazide (ONBIO Inc., 1.4 g, 4.7 mmol) and K Prepared from ₂ CO ₃ (0.55 g, 4 mmol) as a white solid (1.24 g, 63%). Mp 155-157 ° C.

Mass spectrum (API-TIS) m / z 490 (MH), 509 (MNH ₄ ⁺ ), 474 (M-OH), 457 (M-2 × OH). Calculated for C ₁₈ H ₂₂ ClN ₃ O ₇ S ₂ · 1/4 mol EtOAc: C, 44.44; H, 4.70; N, 8.18. Found: C, 44.59; H, 4.49; N, 7.97.

表題の化合物を実施例69bの手順に従うことにより、THF (5 mL)中にて実施例70bの生成物(0.7 g, 1.4 mmol)、発煙HNO₃ (0.45 g, 0.3 mL, 7.1 mmol)およびAc₂O (1.2 g, 1 mL, 11.4 mmol)から白色の泡状物(0.5 g, 60%)として調製した。Mp 70-72℃。

質量スペクトル(API-TIS) m/z 599 (MNH₄ ⁺)。C₁₈H₂₀ClN₅O₁₁S₂に対し算出された分析値: C, 37.15; H, 3.46; N, 12.03。実測値: C, 37.35; H, 3.61; N, 11.76。 70c. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [3- [3,5-bis [(nitrooxy) methyl] phenoxy] propyl] -6-chloro-3,4- Dihydro-, 1,1-dioxide

Follow the procedure of Example 69b for the title compound in THF (5 mL) to give the product of Example 70b (0.7 g, 1.4 mmol), fuming HNO ₃ (0.45 g, 0.3 mL, 7.1 mmol) and Ac. Prepared from ₂ O (1.2 g, 1 mL, 11.4 mmol) as a white foam (0.5 g, 60%). Mp 70-72 ° C.

Mass spectrum (API-TIS) m / z 599 (MNH ₄ ⁺ ). Analytical value calculated for C ₁₈ H ₂₀ ClN ₅ O ₁₁ S ₂ : C, 37.15; H, 3.46; N, 12.03. Found: C, 37.35; H, 3.61; N, 11.76.

表題の化合物を実施例68bの手順に従うことにより、無水DMF (12 mL)中にて実施例68aの生成物(2.5 g, 16.2 mmol)、ジブロモエタン(9.1 g, 4.2 mL, 48.6 mmol)およびK₂CO₃ (2.4 g, 17 mmol)から白色の泡状物(1.6 g, 38%)として調製した。質量スペクトル(API-TIS) m/z 262 (MH⁺)。 Example 71: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 2- [2- [3,5-bis [(nitrooxy) methyl] phenoxy] ethyl] -6-chloro-3, 4-dihydro-, 1,1-dioxide
71a. 1,3-Benzenedimethanol, 5- (2-bromoethoxy)-

The title compound was followed by the procedure of Example 68b in anhydrous DMF (12 mL) to give the product of Example 68a (2.5 g, 16.2 mmol), dibromoethane (9.1 g, 4.2 mL, 48.6 mmol) and K Prepared from ₂ CO ₃ (2.4 g, 17 mmol) as a white foam (1.6 g, 38%). Mass spectrum (API-TIS) m / z 262 (MH ⁺ ).

表題の化合物を実施例69aの手順に従うことにより、無水DMF (10 mL)中にて実施例71aの生成物(1 g, 3.8 mmol)、ヒドロクロロチアジド(ONBIO Inc., 1.36 g, 4.6 mmol)およびK₂CO₃ (0.53 g, 3.8 mmol)から白色の固形物(1.1 g, 60%)として調製した。
Mp 80-82℃。

質量スペクトル(API-TIS) m/z 476 (M-H)、495 (MNH₄ ⁺)、460 (M-OH)、443 (M-2×OH)。C₁₇H₂₀ClN₃O₇S₂・0.3モルEtOAcに対し算出された分析値: C, 43.34; H, 4.48; N, 8.33。実測値: C, 43.36; H, 4.22; N, 7.92。 71b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [2- [3,5-bis (hydroxymethyl) phenoxy] ethyl] -6-chloro-3,4-dihydro- 1,1-dioxide

By following the procedure of Example 69a, the title compound was obtained in Example Dla (10 mL) by adding the product of Example 71a (1 g, 3.8 mmol), hydrochlorothiazide (ONBIO Inc., 1.36 g, 4.6 mmol) and K Prepared from ₂ CO ₃ (0.53 g, 3.8 mmol) as a white solid (1.1 g, 60%).
Mp 80-82 ° C.

Mass spectrum (API-TIS) m / z 476 (MH), 495 (MNH ₄ ⁺ ), 460 (M-OH), 443 (M-2 × OH). _{C 17 H 20 ClN 3 O 7} S 2 · 0.3 moles calculated analytical values for EtOAc: C, 43.34; H, 4.48; N, 8.33. Found: C, 43.36; H, 4.22; N, 7.92.

表題の化合物を実施例69bの手順に従うことにより、THF (5 mL)中にて実施例71bの生成物(0.5 g, 1 mmol)、発煙HNO₃ (0.32 g, 0.22 mL, 5.2 mmol)およびAc₂O (0.85 g, 0.8 mL, 8.4 mmol)から白色の泡状物(0.5 g, 84%)として調製した。Mp 72-75℃。

質量スペクトル(API-TIS) m/z 585 (MNH₄ ⁺)、566 (M-H)。C₁₇H₁₈ClN₅O₁₁S₂・0.3モルEtOAcに対し算出された分析値: C, 37.04; H, 3.54; N, 11.61。実測値: C, 37.27; H, 3.24; N, 11.66。 71c. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [2- [3,5-bis [(nitrooxy) methyl] phenoxy] ethyl] -6-chloro-3,4- Dihydro-, 1,1-dioxide

Follow the procedure of Example 69b for the title compound in THF (5 mL) to give the product of Example 71b (0.5 g, 1 mmol), fuming HNO ₃ (0.32 g, 0.22 mL, 5.2 mmol) and Ac. Prepared from ₂ O (0.85 g, 0.8 mL, 8.4 mmol) as a white foam (0.5 g, 84%). Mp 72-75 ° C.

Mass spectrum (API-TIS) m / z 585 (MNH ₄ ⁺ ), 566 (MH). _{C 17 H 18 ClN 5 O 11} S 2 · 0.3 moles calculated analytical values for EtOAc: C, 37.04; H, 3.54; N, 11.61. Found: C, 37.27; H, 3.24; N, 11.66.

発煙硝酸(90%; 10.1 mL, 200 mmol)を氷冷無水酢酸(30 mL)に加え、氷浴中で15分間撹拌した。その一方で、3,3'-イミノビス-1-プロパノール(Karl Industries, 6.66 g, 50 mmol)の酢酸エチル(50 mL)およびTHF (50 mL)溶液を室温にて濃硝酸(3.13 mL, 50 mmol)で処理した。混合物を0℃に冷却し、発煙硝酸/無水酢酸の溶液を滴下漏斗によって滴下した。0℃で1時間撹拌した後に、エーテル(100 mL)を加えた。白色の固形物をろ過によって集め、さらなるエーテルで洗浄した。固形物を真空下で素早く乾燥して、表題の化合物を白色の固形物(11.21 g, 収率78%)として得た: mp 102-104℃;

質量スペクトル(API-TIS) m/z 224 (MH⁺)。 Example 72: 2H-1,2,4-benzothiadiazine-2-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N, N-bis [3- (nitrooxy) propyl ]-, 1,1-dioxide
72a. 3,3'-Iminobis-1-propanol, dinitrate (ester), nitrate (1: 1) (salt)

Fuming nitric acid (90%; 10.1 mL, 200 mmol) was added to ice-cold acetic anhydride (30 mL) and stirred in an ice bath for 15 minutes. Meanwhile, a solution of 3,3′-iminobis-1-propanol (Karl Industries, 6.66 g, 50 mmol) in ethyl acetate (50 mL) and THF (50 mL) was added to concentrated nitric acid (3.13 mL, 50 mmol) at room temperature. ). The mixture was cooled to 0 ° C. and a fuming nitric acid / acetic anhydride solution was added dropwise via a dropping funnel. After stirring at 0 ° C. for 1 hour, ether (100 mL) was added. A white solid was collected by filtration and washed with more ether. The solid was quickly dried under vacuum to give the title compound as a white solid (11.21 g, 78% yield): mp 102-104 ° C .;

Mass spectrum (API-TIS) m / z 224 (MH ⁺ ).

実施例72aの生成物(9.0 mmol, 2.58 g)の酢酸エチル50 mL懸濁液に、泡立ちが止まり、両層が清澄になるまで過剰の飽和重炭酸ナトリウムを加えた。有機層を分離し、塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を回転蒸発によって除去し、黄白色の残留物をDMF 5 mLに溶解した。この溶液を0℃で実施例31aの生成物および1-(3-(ジメチルアミノ)プロピル)-3-エチルカルボジイミド塩酸塩(EDAC, 0.690 g, 3.6 mmol)のDMF (25 mL)混合物に加えた。反応混合物を0℃で4時間撹拌した。減圧下での溶媒の蒸発後、残留物を酢酸エチルと水との間で分配した。有機層を2 N HCl、水、塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒の蒸発後、残留物をシリカゲル、ジクロロメタン中25〜75%酢酸エチル勾配のカラムクロマトグラフィーによって精製した。溶媒の蒸発により白色の無定形固体を得、これをアセトン/クロロホルム/エーテルから再結晶して、表題の化合物を白色の結晶(0.366 g, 収率22%)として得た: mp 157-160℃。

質量スペクトル(API-TIS) m/z 561 (MH⁺)、578 (MNH₄ ⁺)、1121 (2MH⁺)、1138 (2MNH₄ ⁺)。
C₁₅H₂₁ClN₆O₁₁S₂に対し算出された分析値: C, 32.12; H, 3.77; N, 14.98。実測値: C, 32.06; H, 3.65; N, 14.79。 72b. 2H-1,2,4-Benzothiadiazine-2-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N, N-bis [3- (nitrooxy) propyl]- 1,1-dioxide

To a suspension of the product of Example 72a (9.0 mmol, 2.58 g) in 50 mL of ethyl acetate was added excess saturated sodium bicarbonate until bubbling ceased and both layers were clear. The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was removed by rotary evaporation and the pale yellow residue was dissolved in 5 mL DMF. This solution was added at 0 ° C. to a mixture of the product of Example 31a and 1- (3- (dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (EDAC, 0.690 g, 3.6 mmol) in DMF (25 mL). . The reaction mixture was stirred at 0 ° C. for 4 hours. After evaporation of the solvent under reduced pressure, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2 N HCl, water, brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel, 25-75% ethyl acetate gradient in dichloromethane. Evaporation of the solvent gave a white amorphous solid that was recrystallized from acetone / chloroform / ether to give the title compound as white crystals (0.366 g, 22% yield): mp 157-160 ° C. .

Mass spectrum (API-TIS) m / z 561 (MH ⁺ ), 578 (MNH ₄ ⁺ ), 1121 (2MH ⁺ ), 1138 (2MNH ₄ ⁺ ).
_{C 15 H 21 ClN 6 O 11} S 2 calculated analytical values for: C, 32.12; H, 3.77 ; N, 14.98. Found: C, 32.06; H, 3.65; N, 14.79.

0℃で(4R)-4-(2-ヒドロキシエチル)-2,2-ジメチル-1,3-ジオキソラン(Aldrich, 10 g, 68 mmol)およびトリエチルアミン(919 mL, 136 mmol)のテトラヒドロフラン(500 mL)撹拌溶液に、ピペットによって塩化メタンスルホニル(6.6 mL, 85 mmol)を加えた。臭化リチウム(59 g, 680 mmol)の添加の前に、得られた混合物を同じ温度で30分間撹拌した。反応混合物を室温で21時間撹拌し、次いで回転蒸発により濃縮して揮発性物質の大部分を除去した。残留物を酢酸エチルと水との間で分配した。有機層を分離し、水層を酢酸エチルで抽出した。合わせた有機抽出液を水で2回洗浄し、硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物をフラッシュクロマトグラフィー(シリカゲル、ヘキサン中0〜20% EtOAc勾配)により精製して、表題の化合物(11.3 g, 収率80%)を油状物として得た。

Example 73: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 2-[(3R) -3,4-bis (nitrooxy) butyl] -6-chloro-3,4-dihydro- 1,1-dioxide
73a. 1,3-Dioxolane, 4- (2-Bromoethyl) -2,2-dimethyl-, (4R)-

Tetrahydrofuran (500 mL) of (4R) -4- (2-hydroxyethyl) -2,2-dimethyl-1,3-dioxolane (Aldrich, 10 g, 68 mmol) and triethylamine (919 mL, 136 mmol) at 0 ° C. ) To the stirred solution was added methanesulfonyl chloride (6.6 mL, 85 mmol) by pipette. The resulting mixture was stirred at the same temperature for 30 minutes before the addition of lithium bromide (59 g, 680 mmol). The reaction mixture was stirred at room temperature for 21 hours and then concentrated by rotary evaporation to remove most of the volatile materials. The residue was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed twice with water, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc gradient in hexanes) to give the title compound (11.3 g, 80% yield) as an oil.

実施例73aの生成物(5.43 g, 26.1 mmol)のメタノール(120 mL)撹拌溶液に、p-トルエンスルホン酸一水和物(1 g)を加えた。周囲温度で69時間撹拌した後、混合物を回転蒸発によって濃縮した。残留物を2回クロマトグラフ分離(EtOAc、シリカゲル)にかけ、粗ジオールブロミド(diol-bromide)(1.20 g, 収率27%)を無色の液体として得た。撹拌しながら0℃で硝酸(90%, 2.7 mL, 57 mmol)を無水酢酸(7 mL)に加えた。15分後、粗ジオールブロミド(1.20 g, 7.12 mmol)の酢酸エチル(80 mL)を加え、撹拌を1時間続けた。混合物を400 mLの酢酸エチルおよび氷水(1:1)撹拌混合液に注ぎ入れ、重炭酸ナトリウム固形物(30 g)を10分にわたり分割して加えた。有機層を分離し、重炭酸ナトリウム水溶液で洗浄し、硫酸ナトリウムで乾燥し、ろ過し、濃縮した。残留物をクロマトグラフ分離(シリカゲル、1:3のEtOAc:ヘキサン)にかけ、粗二硝酸ブロミド(dinitrate-bromide) (1.35 g, 収率73%)を黄色の油状物として得た。粗二硝酸ブロミド(1.35 g, 5.22 mmol)、ヒドロクロロチアジド(1.79 g, 6 mmol)のDMF (20 mL)撹拌溶液に、炭酸セシウム(0.85 g, 2.61 mmol)を加えた。室温で25時間撹拌した後に、混合物をEtOAc (200 mL)で処理し、水およびNaCl水溶液で洗浄し、硫酸ナトリウムのパッドを通してゆっくりろ過し、濃縮した。残留物をカラムクロマトグラフィー(CH₂Cl₂中0〜30%のEtOAc)により精製して、固形物を得た。EtOAc:CH₂Cl₂ (1:2)からの固形物の再結晶により、表題の化合物(157 mg, 収率6.3%)を白色の固形物として得た: mp 158-162℃。

質量スペクトル(API-TIS) m/z 476.0および478.1 (それぞれ³⁵Clおよび³⁷ClのMH⁺)。C₁₁H₁₄ClN₅O₁₀S₂に対し算出された分析値: C, 27.77; H, 2.97; N, 14.72。実測値: C, 27.94; H, 2.75; N, 14.46。 73b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[(3R) -3,4-bis (nitrooxy) butyl] -6-chloro-3,4-dihydro-, 1 , 1-dioxide

To a stirred solution of the product of Example 73a (5.43 g, 26.1 mmol) in methanol (120 mL) was added p-toluenesulfonic acid monohydrate (1 g). After stirring for 69 hours at ambient temperature, the mixture was concentrated by rotary evaporation. The residue was chromatographed twice (EtOAc, silica gel) to give crude diol-bromide (1.20 g, 27% yield) as a colorless liquid. Nitric acid (90%, 2.7 mL, 57 mmol) was added to acetic anhydride (7 mL) at 0 ° C. with stirring. After 15 minutes, crude diol bromide (1.20 g, 7.12 mmol) in ethyl acetate (80 mL) was added and stirring was continued for 1 hour. The mixture was poured into a stirred mixture of 400 mL ethyl acetate and ice water (1: 1) and sodium bicarbonate solid (30 g) was added in portions over 10 minutes. The organic layer was separated and washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed (silica gel, 1: 3 EtOAc: hexanes) to give crude dinitrate-bromide (1.35 g, 73% yield) as a yellow oil. Cesium carbonate (0.85 g, 2.61 mmol) was added to a stirred solution of crude dinitrate bromide (1.35 g, 5.22 mmol) and hydrochlorothiazide (1.79 g, 6 mmol) in DMF (20 mL). After stirring at room temperature for 25 hours, the mixture was treated with EtOAc (200 mL), washed with water and aqueous NaCl, slowly filtered through a pad of sodium sulfate, and concentrated. The residue was purified by column chromatography (CH ₂ Cl ₂ in 0-30% EtOAc), to give a solid. Recrystallization of the solid from EtOAc: CH ₂ Cl ₂ (1: 2) gave the title compound (157 mg, 6.3% yield) as a white solid: mp 158-162 ° C.

Mass spectrum (API-TIS) m / z 476.0 and 478.1 ( ^{35 +} and ³⁷ Cl MH ^+, respectively). Analytical values calculated for C ₁₁ H ₁₄ ClN ₅ O ₁₀ S ₂ : C, 27.77; H, 2.97; N, 14.72. Found: C, 27.94; H, 2.75; N, 14.46.

2-(2-ブロモエチル)-1,3-ジオキソラン(Aldrich Chemical Co., 7.24 g, 40 mmol)のアセトニトリル(125 mL)懸濁液に硝酸銀(8.49 g, 50 mmol)を加え、反応混合物を窒素雰囲気下で3時間還流した。固形物を除去するためのろ過の後、溶媒を減圧下で蒸発させ、残留物を酢酸エチルで抽出し、水、塩水で洗浄し、硫酸ナトリウムで乾燥し、ろ過し、真空で濃縮して、ほぼ定量的な収率の表題の化合物を得、これをさらには精製せずに用いた。

Example 74: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [2- (nitrooxy) ethyl]-, 1,1-dioxide
74a. 1,3-Dioxolane-2-ethanol, Nitrate

Silver nitrate (8.49 g, 50 mmol) is added to a suspension of 2- (2-bromoethyl) -1,3-dioxolane (Aldrich Chemical Co., 7.24 g, 40 mmol) in acetonitrile (125 mL), and the reaction mixture is nitrogenated. Refluxed for 3 hours under atmosphere. After filtration to remove solids, the solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered, concentrated in vacuo, An almost quantitative yield of the title compound was obtained and used without further purification.

実施例74aの生成物(1.63 g, 10 mmol)および2-アミノ-6-クロロ-1,3-ベンゼンジスルホンアミド(Aldrich Chemical Co., 1.439 g, 5 mmol)の無水ジオキサン(50 mL)液にAmberlyst(15)湿潤強酸性樹脂(3 g)を加えた。反応混合物を室温で2日間穏やかに撹拌し、次いで別のフラスコにデカントした。樹脂をジオキサン(2 mL)で洗浄し、この洗浄物を反応混合物に加えた。新たなAmberlyst(15)湿潤強酸性樹脂(2 g)を反応混合物に加え、撹拌を室温で24時間続けた。樹脂をろ過により除去し、ろ液を減圧下で濃縮した。得られた残留物を酢酸エチルで処理し、炭酸ナトリウム飽和水溶液、水、塩水で洗浄し、硫酸ナトリウムで乾燥し、ろ過し、真空で濃縮して粗生成物を得た。シリカゲルのカラムクロマトグラフィーでの精製により、3%メタノールのジクロロメタン液で溶出させて油状物1.3 gを得、これを20%酢酸エチルのヘキサン液で摩砕して、表題の化合物(1.1 g, 収率54%)を白色の固形物として得た: mp 113-117℃;

質量スペクトル(API-TIS) m/z 404 (MH)⁺、406 (MH+2)⁺。 74b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [2- (nitrooxy) ethyl]-, 1,1-dioxide

To a solution of the product of Example 74a (1.63 g, 10 mmol) and 2-amino-6-chloro-1,3-benzenedisulfonamide (Aldrich Chemical Co., 1.439 g, 5 mmol) in anhydrous dioxane (50 mL) Amberlyst (15) wet strongly acidic resin (3 g) was added. The reaction mixture was gently stirred at room temperature for 2 days and then decanted into another flask. The resin was washed with dioxane (2 mL) and this wash was added to the reaction mixture. Fresh Amberlyst (15) wet strongly acidic resin (2 g) was added to the reaction mixture and stirring was continued at room temperature for 24 hours. The resin was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was treated with ethyl acetate, washed with saturated aqueous sodium carbonate, water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product. Purification by column chromatography on silica gel eluting with 3% methanol in dichloromethane gave 1.3 g of an oil that was triturated with 20% ethyl acetate in hexane to give the title compound (1.1 g, yield). Yield 54%) as a white solid: mp 113-117 ° C;

Mass spectrum (API-TIS) m / z 404 (MH) ⁺ , 406 (MH + 2) ⁺ .

ヒドロクロロチアジド(ONBIO, Inc., Ontario, Canada) (21.63 g, 72.7 mmol)のDMF 60 mL溶液に炭酸セシウム(14.2 g, 44 mmol)を加え、この懸濁液を0℃に冷却した。臭化アリル(9.67 g, 6.76 mL, 79.9 mmol)を原液として加え、混合物を室温で18時間撹拌した。固形物をろ過によって除去し、溶媒を真空下で除去した。得られた残留物を酢酸エチルと水との間で分配し、有機層を水および塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒の蒸発後、残留物をシリカゲル、ジクロロメタン中25〜50%酢酸エチル勾配のカラムクロマトグラフィーによって精製した。溶媒を回転蒸発によって除去し、残留物をアセトン/クロロホルム/エーテルから再結晶して、表題の化合物(13.39 g, 収率55%)をオフホワイト色の針状結晶として得た: mp 178-180℃:

質量スペクトル(API-TIS) m/z 338 (MH⁺)、355 (MNH₄ ⁺)、692 (2MNH₄ ⁺)。 Example 75: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 2- [2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-, 1,1 -Dioxide; 2H-1,2,4-benzothiadiazine-7-sulfonamide, 2- [2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-4-nitro-, 1,1-dioxide; and 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [2-hydroxy-3- (nitrooxy) propyl]- 4-nitro-, 1,1-dioxide
75a. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- (2-propenyl)-, 1,1-dioxide

Cesium carbonate (14.2 g, 44 mmol) was added to a 60 mL DMF solution of hydrochlorothiazide (ONBIO, Inc., Ontario, Canada) (21.63 g, 72.7 mmol), and the suspension was cooled to 0 ° C. Allyl bromide (9.67 g, 6.76 mL, 79.9 mmol) was added as a stock solution and the mixture was stirred at room temperature for 18 hours. The solid was removed by filtration and the solvent was removed under vacuum. The resulting residue was partitioned between ethyl acetate and water and the organic layer was washed with water and brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel, 25-50% ethyl acetate gradient in dichloromethane. The solvent was removed by rotary evaporation and the residue was recrystallized from acetone / chloroform / ether to give the title compound (13.39 g, 55% yield) as off-white needles: mp 178-180 ℃:

Mass spectrum (API-TIS) m / z 338 (MH +), 355 (MNH 4 +), 692 (2MNH 4 +).

室温で実施例75aの生成物(1.69 g, 5.0 mmol)のアセトン(25 mL)溶液に、四酸化オスミウム(Aldrich, 0.3 mL, 水中4%, 0.05 mmol)、その後ピリジン(触媒、0.01 mL)およびN-メチルモルホリンN-オキシド(TCI, 12.5 mmol, 水中50%, 2.59 mL)を加えた。反応混合物を室温で一晩撹拌した。翌日、さらなるN-メチルモルホリンN-オキシド(0.5 mL)を加えて、撹拌を一晩続けた。反応混合物を飽和チオ硫酸ナトリウム(2 mL)およびいくらかの亜硫酸ナトリウム固形物でクエンチングした。2時間後、反応物を酢酸エチル(3×)で抽出した。有機層を水および塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒の蒸発後、残留物を酢酸エチル/メタノール/エーテルから再結晶して、表題の化合物(0.972 g, 収率52%)を白色の多角柱状結晶として得た: mp 189-194℃;

質量スペクトル(API-TIS) m/z 372 (MH⁺)、389 (MNH₄ ⁺)、760 (2MNH₄ ⁺)。 75b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-2- (2,3-dihydroxypropyl) -3,4-dihydro-, 1,1-dioxide

To a solution of the product of Example 75a (1.69 g, 5.0 mmol) in acetone (25 mL) at room temperature was added osmium tetroxide (Aldrich, 0.3 mL, 4% in water, 0.05 mmol), followed by pyridine (catalyst, 0.01 mL) and N-methylmorpholine N-oxide (TCI, 12.5 mmol, 50% in water, 2.59 mL) was added. The reaction mixture was stirred at room temperature overnight. The next day, additional N-methylmorpholine N-oxide (0.5 mL) was added and stirring was continued overnight. The reaction mixture was quenched with saturated sodium thiosulfate (2 mL) and some sodium sulfite solids. After 2 hours, the reaction was extracted with ethyl acetate (3 ×). The organic layer was washed with water and brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from ethyl acetate / methanol / ether to give the title compound (0.972 g, 52% yield) as white polygonal crystals: mp 189-194 ° C .;

Mass spectrum (API-TIS) m / z 372 (MH ⁺ ), 389 (MNH ₄ ⁺ ), 760 (2MNH ₄ ⁺ ).

トリフルオロ酢酸(1.6 mL, 20.8 mmol)を実施例75bの生成物(3.53 g, 9.49 mmol)のTHF (95 mL)溶液に加え、引き続いて発煙硝酸(2.9 mL, 57.2 mmol)の無水酢酸(15 mL)のあらかじめ混合した溶液の添加を行い、得られた混合物を室温で4.5時間撹拌した。反応混合物を水(30 mL)に注ぎ入れ、THFを減圧下で蒸発させた。得られた水性混合物をEtOAc (150 mL)で抽出した。有機抽出液を水、3 N HCl、塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(25〜65%の勾配、60%でのR_f=0.22)で溶出させて精製し、表題の化合物を淡黄色の固形物(1.7 g, 収率39%)として得た: mp 80-95℃ (分解)。

質量スペクトル(API-TIS) m/z 479 (MNH₄)⁺。C₁₀H₁₂ClN₅O₁₀S₂に対し算出された分析値: C, 26.01; H, 2.62; N, 15.16。実測値: C, 26.02; H, 2.60; N, 14.91。 75c. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-, 1,1-dioxide

Trifluoroacetic acid (1.6 mL, 20.8 mmol) was added to a solution of the product of Example 75b (3.53 g, 9.49 mmol) in THF (95 mL) followed by fuming nitric acid (2.9 mL, 57.2 mmol) in acetic anhydride (15 mL) of the premixed solution was added and the resulting mixture was stirred at room temperature for 4.5 hours. The reaction mixture was poured into water (30 mL) and THF was evaporated under reduced pressure. The resulting aqueous mixture was extracted with EtOAc (150 mL). The organic extract was washed with water, 3 N HCl, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc / hexane (25-65% gradient, R _f = 0.22 at 60%) to give the title compound as a pale yellow solid (1.7 g, yield). 39%): mp 80-95 ° C. (decomposition).

Mass spectrum (API-TIS) m / z 479 (MNH ₄ ) ⁺ . _{C 10 H 12 ClN 5 O 10} S 2 calculated analytical values for: C, 26.01; H, 2.62 ; N, 15.16. Found: C, 26.02; H, 2.60; N, 14.91.

実施例75cの生成物(0.98 g)はChiral Technologies, West Chester, PAにより、エタノールを溶離液として用いて、ChiralPak ADカラムで分離された。ChiralPak AD-H 4.6 mm×25 cmカラムにて、エタノールで溶出させて分析した場合、鏡像異性体1 (0.46 g)は4.93分の保持時間を有し、鏡像異性体2 (0.46 g)は6.24分の保持時間を有していた。 75d 2H-1,2,4-benzothiadiazine-7-sulfonamide, 2-[(2R) -2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-, 1, 1-dioxide (enantiomer 1) and 2H-1,2,4-benzothiadiazine-7-sulfonamide, 2-[(2S) -2,3-bis (nitrooxy) propyl] -6-chloro- 3,4-dihydro-, 1,1-dioxide (enantiomer 2)

The product of Example 75c (0.98 g) was separated on a ChiralPak AD column by Chiral Technologies, West Chester, PA using ethanol as the eluent. When analyzed on a ChiralPak AD-H 4.6 mm x 25 cm column eluting with ethanol, Enantiomer 1 (0.46 g) has a retention time of 4.93 min and Enantiomer 2 (0.46 g) is 6.24. Had a retention time of minutes.

表題の化合物は実施例75cの反応物の副生成物であり、カラムクロマトグラフィーにより分離した。R_f=0.45 (60% EtOAc/ヘキサン中)の画分を集めて、表題の化合物を黄色の固形物(1.0 g, 収率21%)として得た: mp >100℃ (分解)。

質量スペクトル(API-TIS) m/z 524 (MNH₄)⁺。 75e. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-4-nitro-, 1 , 1-dioxide

The title compound is a byproduct of the reaction in Example 75c and was separated by column chromatography. Fractions of R _f = 0.45 (in 60% EtOAc / hexanes) were collected to give the title compound as a yellow solid (1.0 g, 21% yield): mp> 100 ° C. (dec).

Mass spectrum (API-TIS) m / z 524 (MNH ₄ ) ⁺ .

表題の化合物は実施例75cの反応物の副生成物であり、カラムクロマトグラフィーにより分離した。R_f=0.33 (60% EtOAc/ヘキサン中)の画分を集めて、表題の化合物を黄色の固形物(0.33 g, 収率8%)として得た:

質量スペクトル(API-TIS) m/z 479 (MNH₄)⁺。 75f. 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [2-hydroxy-3- (nitrooxy) propyl] -4-nitro-, 1,1-dioxide

The title compound is a byproduct of the reaction in Example 75c and was separated by column chromatography. Fractions with R _f = 0.33 (in 60% EtOAc / hexanes) were collected to give the title compound as a yellow solid (0.33 g, 8% yield):

Mass spectrum (API-TIS) m / z 479 (MNH ₄ ) ⁺ .

表題の化合物をSmith, P. et al, J. Am. Chem. Soc., 106(7): 1986-1991 (1984)により記載されているように4-オキソ-2,2,6,6-テトラメチル-1-オキシ-ピペリジン(tempone) (Aldrich)から調製した。生成物は赤色の油状物であった。質量スペクトル(API-TIS) m/z 199 (MH⁺)。IR (neat) 1728 (C=O) cm^-1。 Example 76: 1-piperidinyloxy, 4-[[7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazine -3-yl] methyl] -2,2,6,6-tetramethyl-
76a. 1-Piperidinyloxy, 2,2,6,6-tetramethyl-4- (2-oxoethyl)-

The title compound may be prepared as described by Smith, P. et al, J. Am. Chem. Soc., 106 (7): 1986-1991 (1984). Prepared from tetramethyl-1-oxy-piperidine (tempone) (Aldrich). The product was a red oil. Mass spectrum (API-TIS) m / z 199 (MH ⁺ ). IR (neat) 1728 (C = O) cm ^-1 .

55-60℃で4-クロロ-6-アミノベンゼン-1,3-ジスルホンアミド(Aldrich, 1 g, 3.5 mmol)および実施例76aの生成物(1.4 g, 7.0 mmol)の無水ジオキサン(10 mL)混合物に、30分間にわたって濃HCl (10滴)を滴下した。次いで、混合物を60℃で1時間加熱した。溶媒を蒸発させた。残留物を10% NaHCO₃で中和し、生成物をEtOAcで抽出した。合わせた有機層を水で洗浄し、Na₂SO₄で乾燥し、ろ過した。溶媒の蒸発後の残留物をシリカゲルのクロマトグラフィーにより分離しヘキサン:EtOAc:MeOH (4.5:5:0.5)で溶出させて、表題の化合物(0.26 g, 収率16%)を淡橙色〜赤色の固形物として得た: mp 238-240℃。

質量スペクトル(API-TIS) m/z 464 (M-H)、465 (M⁺)。C₁₇H₂₆ClN₄O₅S₂・1/4モルEtOAcに対し算出された分析値 C, 44.30; H, 5.78; N, 11.48。実測値: C, 44.43; H, 5.68; N, 11.43。 76b. 1-piperidinyloxy, 4-[[7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazine-3 -Il] methyl] -2,2,6,6-tetramethyl-

4-Chloro-6-aminobenzene-1,3-disulfonamide (Aldrich, 1 g, 3.5 mmol) and the product of Example 76a (1.4 g, 7.0 mmol) at 55-60 ° C. in anhydrous dioxane (10 mL) To the mixture was added concentrated HCl (10 drops) dropwise over 30 minutes. The mixture was then heated at 60 ° C. for 1 hour. The solvent was evaporated. The residue was neutralized with 10% NaHCO ₃ and the product was extracted with EtOAc. The combined organic layers were washed with water, dried over Na ₂ SO ₄ and filtered. The residue after evaporation of the solvent was separated by chromatography on silica gel eluting with hexane: EtOAc: MeOH (4.5: 5: 0.5) to give the title compound (0.26 g, 16% yield) as a pale orange to red Obtained as a solid: mp 238-240 ° C.

Mass spectrum (API-TIS) m / z 464 (MH), 465 (M ⁺ ). Calculated for C ₁₇ H ₂₆ ClN ₄ O ₅ S ₂ · 1/4 mol EtOAc C, 44.30; H, 5.78; N, 11.48. Found: C, 44.43; H, 5.68; N, 11.43.

実施例76bの作業過程後の残留物をシリカゲルのクロマトグラフィーにより分離しCH₂Cl₂:EtOAc:MeOH (4.5:4.5:1)で溶出させて、表題の化合物(0.4 g, 収率24%)を白色の固形物として得た: mp 174-176℃。

質量スペクトル(API-TIS) m/z 465 (M-H)、467 (MH⁺)。 Example 77: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[(1-hydroxy-2,2,6,6-tetramethyl -4-piperidinyl) methyl]-, 1,1-dioxide

The working residue of Example 76b was separated by chromatography on silica gel and eluted with CH ₂ Cl ₂ : EtOAc: MeOH (4.5: 4.5: 1) to give the title compound (0.4 g, 24% yield). Was obtained as a white solid: mp 174-176 ° C.

Mass spectrum (API-TIS) m / z 465 (MH), 467 (MH ⁺ ).

ヒドロクロロチアジド(15.0 g, 50.38 mmol)および炭酸セシウム(8.21 g, 25.19 mmol)のDMF (120 mL)撹拌混合物に、注射器によってブロモマロン酸ジメチル(tech., 90%; 6.60 mL, 50.38 mmol)を加えた。反応混合物を室温で18時間撹拌し、水に注ぎ入れ、2回酢酸エチルで抽出した。合わせた有機抽出液をNaCl水溶液で洗浄し、Na₂SO₄で乾燥し、ろ過し、回転蒸発により濃縮した。残留物をカラムクロマトグラフィー(シリカゲル、塩化メチレン中0〜30%勾配の酢酸エチル)により精製して、表題の化合物(3.06 g, 収率14%)を白色の固形物として得た。

質量スペクトル(API-TIS) m/z 428.0および430.0 (それぞれ³⁵Clおよび³⁷ClのMH⁺)。 Example 78: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [2-hydroxy-1- (hydroxymethyl) ethyl]-, 1 , 1-dioxide
78a. Propandioic acid, [7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazin-2-yl]-, dimethyl ester

To a stirred mixture of hydrochlorothiazide (15.0 g, 50.38 mmol) and cesium carbonate (8.21 g, 25.19 mmol) in DMF (120 mL) was added dimethyl bromomalonate (tech., 90%; 6.60 mL, 50.38 mmol) via syringe. The reaction mixture was stirred at room temperature for 18 hours, poured into water and extracted twice with ethyl acetate. The combined organic extracts were washed with aqueous NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated by rotary evaporation. The residue was purified by column chromatography (silica gel, 0-30% gradient of ethyl acetate in methylene chloride) to give the title compound (3.06 g, 14% yield) as a white solid.

Mass spectrum (API-TIS) m / z 428.0 and 430.0 ( ^{35 +} and ³⁷ Cl MH ^+, respectively).

0℃でエタノール(15 mL)およびTHF (15 mL)混合液中の実施例78aの生成物(1.00 g, 2.34 mmol)の撹拌溶液に、NaBH₄を分割して加えた。反応混合物を0℃で2時間、次に室温で18時間撹拌した。塩酸(6 N, 3 mL)を滴下し、得られた乳白色の懸濁液をろ過した。ろ過ケークをエタノールおよびTHFで徹底的に洗浄し、ろ液を回転蒸発によって濃縮した。カラムクロマトグラフィー(シリカゲル、EtOAc中0〜30%勾配のTHF)とそれに続くMeOHからの結晶化により、表題の化合物(62 mg, 収率7%)を白色の固形物として得た。Mp 139-143℃。

質量スペクトル(API-TIS) m/z 372.3および374.0 (それぞれ³⁵Clおよび³⁷ClのMH⁺)。 78b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [2-hydroxy-1- (hydroxymethyl) ethyl]-, 1,1 -Dioxide

To a stirred solution of the product of Example 78a (1.00 g, 2.34 mmol) in a mixture of ethanol (15 mL) and THF (15 mL) at 0 ° C., NaBH ₄ was added in portions. The reaction mixture was stirred at 0 ° C. for 2 hours and then at room temperature for 18 hours. Hydrochloric acid (6 N, 3 mL) was added dropwise, and the resulting milky white suspension was filtered. The filter cake was washed thoroughly with ethanol and THF and the filtrate was concentrated by rotary evaporation. Column chromatography (silica gel, 0-30% gradient of THF in EtOAc) followed by crystallization from MeOH afforded the title compound (62 mg, 7% yield) as a white solid. Mp 139-143 ° C.

Mass spectrum (API-TIS) m / z 372.3 and 374.0 ( ³⁵ Cl and ³⁷ Cl MH ^+, respectively).

イソフタル酸5-ブロモジメチル(11.2 g, 41.0 mmol)、アリルアルコール(3.62 mL, 53.2 mmol)、炭酸ナトリウム(11.0 g, 104 mmol)、塩化ベンジルトリエチルアンモニウム(10.2 g, 45 mmol)および二酢酸パラジウム(0.45 g, 2.0 mmol)のDMF (80 mL)混合物を80℃に1.5時間加熱した。反応混合物をセライトを通してろ過し、EtOAc (100 mL)で洗浄した。合わせたろ液を真空下で蒸発乾固した。残留物をEtOAc (150 mL)と水(150 mL×3)との間で分配した。有機抽出液を塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(20〜40% EtOAc/ヘキサンの勾配; 25%でのR_f=0.15)で溶出させて精製し、表題の化合物を結晶性固形物(7.13 g, 収率70%)として得た: mp 70-71 ℃;

質量スペクトル(API-TIS) m/z 251 (MH)⁺。 Example 79: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3- [2- [3,5-bis (hydroxymethyl) phenyl] ethyl] -6-chloro-3,4- Dihydro-, 1,1-dioxide
79a. 1,3-Benzenedicarboxylic acid, 5- (3-oxopropyl)-, dimethyl ester

5-bromodimethyl isophthalate (11.2 g, 41.0 mmol), allyl alcohol (3.62 mL, 53.2 mmol), sodium carbonate (11.0 g, 104 mmol), benzyltriethylammonium chloride (10.2 g, 45 mmol) and palladium diacetate ( 0.45 g, 2.0 mmol) of DMF (80 mL) was heated to 80 ° C. for 1.5 h. The reaction mixture was filtered through celite and washed with EtOAc (100 mL). The combined filtrates were evaporated to dryness under vacuum. The residue was partitioned between EtOAc (150 mL) and water (150 mL × 3). The organic extract was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc / hexane (20-40% EtOAc / hexane gradient; R _f = 0.15 at 25%) to give the title compound as a crystalline solid (7.13 g, Yield 70%): mp 70-71 ° C;

Mass spectrum (API-TIS) m / z 251 (MH) ⁺ .

MeOH (50 mL)中にて実施例79aの生成物(6.14 g, 24.5 mmol)、オルトギ酸トリメチル(5.5 mL, 50.3 mmol)および濃硫酸(0.07 mL, 1.3 mmol)を1.5時間加熱還流し、次いで室温に冷却し、Na₂CO₃ (0.48 g, 4.5 mmol)を加えた。得られた混合物を室温で20分間撹拌し、次いで蒸発乾固した。残留物をEtOAc (100 mL)に溶解し、Na₂SO₄で乾燥し、ろ過し、濃縮し、真空下で乾燥した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(20〜35% EtOAc/ヘキサンの勾配; 25%でのR_f=0.25)で溶出させて精製し、表題の化合物を白色の結晶性固形物(6.77 g, 収率93%)として得た: mp 59-61℃;

質量スペクトル(API-TIS) m/z 265 (M-OCH₃)⁺。 79b. 1,3-Benzenedicarboxylic acid, 5- (3,3-dimethoxypropyl)-, dimethyl ester

The product of Example 79a (6.14 g, 24.5 mmol), trimethyl orthoformate (5.5 mL, 50.3 mmol) and concentrated sulfuric acid (0.07 mL, 1.3 mmol) were heated at reflux for 1.5 hours in MeOH (50 mL), then Cool to room temperature and add Na ₂ CO ₃ (0.48 g, 4.5 mmol). The resulting mixture was stirred at room temperature for 20 minutes and then evaporated to dryness. The residue was dissolved in EtOAc (100 mL), dried over Na ₂ SO ₄ , filtered, concentrated and dried under vacuum. The product was purified by silica gel column chromatography eluting with EtOAc / hexane (20-35% EtOAc / hexane gradient; R _f = 0.25 at 25%) to give the title compound as a white crystalline solid (6.77 g, 93% yield): mp 59-61 ° C;

Mass spectrum (API-TIS) m / z 265 (M-OCH ₃ ) ⁺ .

スーパーヒドリド(Super-hydride) (THF中1 M, 8.6 mL, 8.6 mmol)をTHF (20 mL)中の実施例79bの生成物(0.553 g, 1.9 mmol)に加え、室温で一晩撹拌した。反応混合物を水(5 mL)およびTHFでクエンチングし、減圧下で蒸発させた。残留物をEtOAc (100 mL)と水(50 mL)との間で分配した。有機層を塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(30%〜70% EtOAc/ヘキサンの勾配; 67%でのR_f=0.15)で溶出させて精製し、表題の化合物を清澄な油状物(0.33 g, 収率74%)として得た。

質量スペクトル(API-TIS) m/z 258 (MNH₄)⁺。 79c. 1,3-Benzenedimethanol, 5- (3,3-dimethoxypropyl)-

Super-hydride (1 M in THF, 8.6 mL, 8.6 mmol) was added to the product of Example 79b (0.553 g, 1.9 mmol) in THF (20 mL) and stirred overnight at room temperature. The reaction mixture was quenched with water (5 mL) and THF and evaporated under reduced pressure. The residue was partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc / hexane (gradient 30% to 70% EtOAc / hexane; R _f = 0.15 at 67%) to give the title compound as a clear oil (0.33 g , Yield 74%).

Mass spectrum (API-TIS) m / z 258 (MNH ₄ ) ⁺ .

実施例79cの生成物(0.65 g, 2.71 mmol)、p-トルエンスルホン酸一水和物(0.524 g, 2.75 mmol)および4-アミノ-6-クロロ-1,3-ベンゼンジスルホンアミド(0.77 g, 2.69 mmol)の1,4-ジオキサン(27 mL)溶液を1時間加熱還流した。反応混合物を減圧下で蒸発乾固した。得られた残留物をアセトン(50 mL)に溶解し、酢酸ナトリウム(0.32 g, 3.9 mmol)とともに30分間撹拌した。混合物をNa₂SO₄で乾燥し、ろ過し、濃縮した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(40〜100% EtOAc/ヘキサンの勾配、100%でのR_f=0.13)で溶出させて精製し、表題の化合物を白色の固形物(0.6 g, 収率48%)として得た: mp 218℃;

質量スペクトル(API-TIS) m/z 460 (M-H)^-。C₁₇H₂₀ClN₃O₆S₂に対し算出された分析値: C, 44.20; H, 4.36; N, 9.10。実測値: C, 44.12; H, 4.26; N, 8.87。 79d. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- [2- [3,5-bis (hydroxymethyl) phenyl] ethyl] -6-chloro-3,4-dihydro- 1,1-dioxide

The product of Example 79c (0.65 g, 2.71 mmol), p-toluenesulfonic acid monohydrate (0.524 g, 2.75 mmol) and 4-amino-6-chloro-1,3-benzenedisulfonamide (0.77 g, 2.69 mmol) in 1,4-dioxane (27 mL) was heated to reflux for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure. The obtained residue was dissolved in acetone (50 mL) and stirred with sodium acetate (0.32 g, 3.9 mmol) for 30 minutes. The mixture was dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc / hexane (40-100% EtOAc / hexanes gradient, R _f = 0.13 at 100%) to give the title compound as a white solid (0.6 g, Yield 48%): mp 218 ° C;

Mass spectrum (API-TIS) m / z 460 (MH) ^- . Analytical values calculated for C ₁₇ H ₂₀ ClN ₃ O ₆ S ₂ : C, 44.20; H, 4.36; N, 9.10. Found: C, 44.12; H, 4.26; N, 8.87.

発煙硝酸(90%, 1.4 mL, 27.0 mmol)の無水酢酸(15 mL)のあらかじめ混合した溶液をEtOAc (50 mL)中の実施例79cの生成物(2.04 g, 8.5 mmol)に加え、室温で25分間撹拌した。反応混合物を3 N HCl (50 mL)とともに1時間撹拌し、その後、減圧下で蒸発させた。得られた混合物をEtOAc (200 mL)で抽出した。有機抽出液を塩水で洗浄し、Na₂SO₄で乾燥し、ろ過し、濃縮した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(20〜50% EtOAc/ヘキサンの勾配、40%でのR_f=0.35)で溶出させて精製し、表題の化合物を淡黄色の油状物(1.64 g, 収率68%)として得た。

Example 80: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3- [2- [3,5-bis [(nitrooxy) methyl] phenyl] ethyl] -6-chloro-3, 4-dihydro-, 1,1-dioxide
80a. Benzenepropanal, 3,5-bis [(nitrooxy) methyl]-

A premixed solution of fuming nitric acid (90%, 1.4 mL, 27.0 mmol) in acetic anhydride (15 mL) was added to the product of Example 79c (2.04 g, 8.5 mmol) in EtOAc (50 mL) at room temperature. Stir for 25 minutes. The reaction mixture was stirred with 3 N HCl (50 mL) for 1 hour and then evaporated under reduced pressure. The resulting mixture was extracted with EtOAc (200 mL). The organic extract was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc / hexane (gradient 20-50% EtOAc / hexanes, R _f = 0.35 at 40%) to give the title compound as a pale yellow oil (1.64 g , Yield 68%).

実施例80aの生成物(0.5 g, 1.76 mmol)、p-トルエンスルホン酸一水和物(0.34 g, 1.79 mmol)および4-アミノ-6-クロロ-1,3-ベンゼンジスルホンアミド(0.51 g, 1.78 mmol)の1,4-ジオキサン(15 mL)液を1時間加熱還流した。反応混合物を減圧下で蒸発乾固した。残留物をアセトン(50 mL)に溶解し、酢酸ナトリウム(0.23 g, 2.74 mmol)とともに30分間撹拌した。得られた混合物をNa₂SO₄で乾燥し、ろ過し、濃縮した。生成物をシリカゲルカラムクロマトグラフィーによりEtOAc/ヘキサン(50〜80%の勾配、67%でのR_f=0.35)で溶出させて精製し、表題の化合物を白色の固形物(0.34 g, 収率35%)として得た: mp 101-104℃;

質量スペクトル(API-TIS) m/z 550 (M-H)^-。 80b. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- [2- [3,5-bis [(nitrooxy) methyl] phenyl] ethyl] -6-chloro-3,4- Dihydro-, 1,1-dioxide

The product of Example 80a (0.5 g, 1.76 mmol), p-toluenesulfonic acid monohydrate (0.34 g, 1.79 mmol) and 4-amino-6-chloro-1,3-benzenedisulfonamide (0.51 g, 1.78 mmol) of 1,4-dioxane (15 mL) was heated to reflux for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in acetone (50 mL) and stirred with sodium acetate (0.23 g, 2.74 mmol) for 30 minutes. The resulting mixture was dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by silica gel column chromatography eluting with EtOAc / hexanes (50-80% gradient, R _f = 0.35 at 67%) to give the title compound as a white solid (0.34 g, yield 35 %) Obtained as: mp 101-104 ° C;

Mass spectrum (API-TIS) m / z 550 (MH) ^- .

DMFの中に炭酸セシウム(1.297 g, 3.98 mmol)を固形物として加え、その後エピブロモヒドリン(0.604 ml, 7.30 mmol)、ヒドロクロロチアジド(1.976 g, 6.64 mmol)を加えた。反応混合物を室温で一晩撹拌した。反応混合物を、媒質用ガラスフリット(medium glass frit)を通してろ過し、高真空下で回転蒸発によって濃縮した。残留物を酢酸エチルと水との間で分配した。有機層を水、塩水で洗浄し、硫酸マグネシウムで乾燥した。LCMS分析によって、所望の生成物が存在すると分かった。溶媒の蒸発後、残留物をシリカゲル、ジクロロメタン中5〜10%メタノール勾配(ジクロロメタン中10%メタノールでの生成物のR_f=0.35)のカラムクロマトグラフィーによって精製した。適切な画分を合わせ、濃縮し、残留物をアセトン/クロロホルム/エーテルから再結晶して、表題の生成物(0.710 g, 2.01 mmol, 収率30%)を白色の多角柱状結晶として得た: mp 192-197℃;

質量スペクトル(API-TIS) m/z 354 (MH⁺)、371 (MNH₄ ⁺)、724 (2MNH₄ ⁺)。C₁₀H₁₂ClN₃O₅S₂に対し算出された分析値: C, 33.95; H, 3.42; N, 11.88。実測値: C, 33.99; H, 3.19; N, 11.74。 Example 81: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- (oxiranylmethyl)-, 1,1-dioxide

Cesium carbonate (1.297 g, 3.98 mmol) was added as a solid in DMF, followed by epibromohydrin (0.604 ml, 7.30 mmol) and hydrochlorothiazide (1.976 g, 6.64 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a medium glass frit and concentrated by rotary evaporation under high vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. LCMS analysis showed the desired product was present. After evaporation of the solvent, the residue was purified by column chromatography on silica gel, 5-10% methanol gradient in dichloromethane (R _f = 0.35 of product with 10% methanol in dichloromethane). Appropriate fractions were combined and concentrated, and the residue was recrystallized from acetone / chloroform / ether to give the title product (0.710 g, 2.01 mmol, 30% yield) as white polygonal crystals: mp 192-197 ° C;

Mass spectrum (API-TIS) m / z 354 (MH ⁺ ), 371 (MNH ₄ ⁺ ), 724 (2MNH ₄ ⁺ ). _{C 10 H 12 ClN 3 O 5} S 2 calculated analytical values for: C, 33.95; H, 3.42 ; N, 11.88. Found: C, 33.99; H, 3.19; N, 11.74.

クロロスルホン酸(75 ml, 1130 mmol)を0℃に冷却し、N-メチル-3-クロロアニリン(10.0 g, 70.6 mmol)の緩徐な添加の間に撹拌した。反応混合物を118〜135℃で4.5時間加熱し、室温で一晩静置させた。混合物を氷水浴にゆっくり注ぎ入れ、得られた半固形物を熱いクロロホルム(2×200 mL)で抽出した。合わせた有機抽出液をMgSO₄で乾燥し、溶媒を減圧下でほぼ乾固するまで除去した。生成物を精製または分析はせずに次の段階で用いた。 Example 82: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-4-methyl-3- [4- (nitrooxy) butyl]-, 1, 1-dioxide
82a. 1,3-Benzenedisulfonyl dichloride, 4-chloro-6- (methylamino)-

Chlorosulfonic acid (75 ml, 1130 mmol) was cooled to 0 ° C. and stirred during the slow addition of N-methyl-3-chloroaniline (10.0 g, 70.6 mmol). The reaction mixture was heated at 118-135 ° C. for 4.5 hours and allowed to stand overnight at room temperature. The mixture was slowly poured into an ice-water bath and the resulting semi-solid was extracted with hot chloroform (2 × 200 mL). The combined organic extracts were dried over MgSO ₄ and the solvent was removed under reduced pressure to near dryness. The product was used in the next step without purification or analysis.

水酸化アンモニウム(37.9 ml, 282 mmol)を氷浴中で0℃に冷却し、実施例82aの生成物(23.91 g, 70.6 mmol)を滴下した。混合物を4時間室温に加温させた。得られた固形物をろ過により集め、MeOH/H₂O中で摩砕した。固形物をろ過により集めて、表題の化合物(1.0 g, 収率4.72%)を淡灰色の固形物として得た:

質量スペクトル(API-TIS) m/z 300 (MH⁺)。 82b. 1,3-Benzenedisulfonamide, 4-chloro-6- (methylamino)-

Ammonium hydroxide (37.9 ml, 282 mmol) was cooled to 0 ° C. in an ice bath and the product of Example 82a (23.91 g, 70.6 mmol) was added dropwise. The mixture was allowed to warm to room temperature for 4 hours. The resulting solid was collected by filtration and triturated in MeOH / H ₂ O. The solid was collected by filtration to give the title compound (1.0 g, 4.72% yield) as a light gray solid:

Mass spectrum (API-TIS) m / z 300 (MH ⁺ ).

実施例82bの生成物(1.00 g, 3.34 mmol)を水(15 mL)中で処理し、加熱還流した。これにホルムアルデヒド(0.323 ml, 4.34 mmol)および塩化アンモニウム(0.196 g, 3.67 mmol)の水5 mL溶液を加えた。混合物を5時間還流で加熱し撹拌し、室温に冷却し、週末にかけて撹拌させておいた。固形物をろ過によって除去し、アセトン/クロロホルム/エーテルから再結晶して、表題の化合物(0.62 g, 収率59.2%)を白色の固形物として得た:

質量スペクトル(API-TIS) m/z 312 (MH⁺)および329 (MNH₄ ⁺)。 82c. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-4-methyl-, 1,1-dioxide

The product of Example 82b (1.00 g, 3.34 mmol) was treated in water (15 mL) and heated to reflux. To this was added a 5 mL solution of formaldehyde (0.323 ml, 4.34 mmol) and ammonium chloride (0.196 g, 3.67 mmol) in water. The mixture was heated and stirred at reflux for 5 hours, cooled to room temperature and allowed to stir over the weekend. The solid was removed by filtration and recrystallized from acetone / chloroform / ether to give the title compound (0.62 g, 59.2% yield) as a white solid:

Mass spectrum (API-TIS) m / z 312 (MH ⁺ ) and 329 (MNH ₄ ⁺ ).

実施例82bの生成物(1.5 g, 5.00 mmol)および実施例17aの生成物(0.810 g, 5.50 mmol)をジオキサン(50 mL)および濃HCl (2 mL)の中で合わせ、この反応混合物を1時間還流で加熱した。混合物を室温に冷却し、塩水で洗浄し、有機層を分離した。溶媒を減圧下で除去し、残留物をEtOAcの中で処理し、炭酸ナトリウム、水、および塩水で洗浄し、MgSO₄で乾燥した。溶媒を減圧下で除去して粗生成物を得た。カラムクロマトグラフィー(1:1のTHF/ヘキサン〜100% THF勾配)での精製によって、表題の化合物(0.41 g, 収率19.10%)を白色の泡状物として得た:

質量スペクトル(API-TIS) m/z 429 (MH⁺)。 82d. 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-4-methyl-3- [4- (nitrooxy) butyl]-, 1,1- Dioxide

The product of Example 82b (1.5 g, 5.00 mmol) and the product of Example 17a (0.810 g, 5.50 mmol) were combined in dioxane (50 mL) and concentrated HCl (2 mL) and the reaction mixture was combined with 1 Heated at reflux for hours. The mixture was cooled to room temperature, washed with brine and the organic layer was separated. The solvent was removed under reduced pressure and the residue was treated in EtOAc, washed with sodium carbonate, water, and brine and dried over MgSO ₄ . The solvent was removed under reduced pressure to give the crude product. Purification by column chromatography (1: 1 THF / hexanes to 100% THF gradient) gave the title compound (0.41 g, 19.10% yield) as a white foam:

Mass spectrum (API-TIS) m / z 429 (MH ⁺ ).

表題の化合物は実施例79dの手順に従うことによって、(R)-(+)-2,2-ジメチル-1,3-ジオキソラン-4-カルボキシアルデヒドとの実施例82bの生成物の縮合により合成される。この生成物は酸性条件下にて水メタノール中で2H-1,2,4-ベンゾチアジアジン-7-スルホンアミド, 6-クロロ-3-[(1R)-1,2-ジヒドロキシエチル]-3,4-ジヒドロ-4-メチル-, 1,1-ジオキシドに加水分解される。得られた化合物を実施例75cの手順に従い硝酸で処理すると、表題の化合物が得られる。 Example 83: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3-[(1R) -1,2-bis (nitrooxy) ethyl] -6-chloro-3,4-dihydro- 4-methyl-, 1,1-dioxide

The title compound is synthesized by condensation of the product of Example 82b with (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde by following the procedure of Example 79d. The This product is 2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3-[(1R) -1,2-dihydroxyethyl]-in aqueous methanol under acidic conditions Hydrolyzed to 3,4-dihydro-4-methyl-, 1,1-dioxide. Treatment of the resulting compound with nitric acid according to the procedure of Example 75c gives the title compound.

表題の化合物は、(S)-(+)-2,2-ジメチル-1,3-ジオキソラン-4-カルボキシアルデヒドが出発材料として使われることを除いて、実施例84と同じ手順に従うことにより合成される。 Example 84: 2H-1,2,4-benzothiadiazine-7-sulfonamide, 3-[(1S) -1,2-bis (nitrooxy) ethyl] -6-chloro-3,4-dihydro- 4-methyl-, 1,1-dioxide

The title compound was synthesized by following the same procedure as Example 84, except that (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde was used as the starting material. Is done.

Example 85: Measurement of diuresis The procedure was approved by the in-house animal care and use committee of NitroMed Inc. Male Wistar rats (180-200 g) were purchased from Charles River Laboratories (Kingston, NY or Raleigh, NC) and allowed to acclimate in the facility for at least 72 hours. Rats were randomly housed 2-3 in a light / dark room with a light / dark cycle of 12 hours per cage and had free access to food and water.

  Prior to the experiment, each rat was housed in a metabolic cage and freely fed food and water and allowed to acclimate for 24-48 hours. During this acclimation period, rats were fed a powder diet instead of pelleted food to prevent contamination of the urine sample. All rats were fasted 18 hours before the experiment. In addition, water was removed 90 minutes prior to oral administration of the test compound or vehicle.

  Test compounds were prepared immediately prior to administration in 0.5% Methocel (F4M Premium Hydroxypropyl Methylcellulose, Lot Number PF12012N12; Dow Chemical Company, USA), and a glass / Teflon pestle motor was prepared. Homogenized with a homogenizer. Gently vortexed test compound was administered intragastricly (p.o .; 30 mg / kg or 3 mg / kg) at a dose of 3 ml per rat via an 18 gauge forced feeding syringe. Urine volume (ml) was monitored and urine collected for 6 hours for later electrolyte analysis. Table 1 shows the amount of urine collected over 6 hours. Data are expressed as mean ± SEM; n = 6 or 7.

Example 86: Rat aldosterone and renin inhibition under in vivo conditions The effects of chronic administration of the compound of Example 51 and hydrochlorothiazide (HCT) on plasma aldosterone and renin levels were investigated in male Wistar rats. The compound was administered by a mini-osmotic pump implanted subcutaneously into the rat scapula region using aseptic technique. Molar equivalent doses of HCT and the compound of Example 51 (10 mg / kg / day) in 50% DMSO / PEG300 were delivered by Alzet minipump for 28 days and compared to vehicle-treated animals. A 250 μl blood sample was obtained from the tail vein cannula for analysis of aldosterone and plasma renin levels (day 0). Terminal plasma was collected on day 29 for analysis of aldosterone and plasma renin levels. Plasma renin and aldosterone were measured using commercially available kits (Cayman Chemical; Ann Arbor, MI and Alpha Diagnostics; San Antonio, TX, respectively).

  Table 2 shows that plasma aldosterone and renin measured at day 29 were significantly reduced after treatment with the compound of Example 51 compared to vehicle or HCT-treated rats. Suggests that it appeared to have a beneficial effect on the renin-angiotensin system by reducing plasma aldosterone and renin levels compared to hydrochlorothiazide.

^aP < 0.05 媒体対照と対比した実施例51の化合物
^bP < 0.001 対HCT処置動物
^cP < 0.05 対HCT処置動物

^a P <0.05 Example 51 compound compared to vehicle control
^b P <0.001 vs. HCT-treated animals
^c P <0.05 versus HCT-treated animals

Example 87: In vitro relaxation in rat aorta Male Wistar rats (250-400 g) were anesthetized with ketamine (10 mg / kg ip) and exsanguinated to remove the abdominal aorta. After removal of fat and connective tissue, the aorta is cut into 3-4 mm lengths and Krebs' modified solution (composition, mM: NaCl 119, CaCl ₂ 2.5, KCl 4.5, NaHCO ₃ 25, MgCl ₂ 1.25, NaHPO ₄ It was suspended in a 10 ml organ bath containing 1.0, D-glucose 11.1). The Krebs' solution was maintained at 37 ° C. and was gassed with 5% CO ₂ in O ₂ . The aortic ring was suspended with an initial static tension of 1.5 g and washed every 15 minutes for a 60 minute equilibration time. After the equilibration time, the aortic ring was contracted with 1 μM phenylephrine and the contraction was allowed to reach a plateau before cumulatively (1-30,000 nM) of test compound dissolved in DMSO. Results were calculated as the percentage of maximum relaxation caused by 10 mM papaverine added at the end of the experiment.

The ability of the compound of Example 46b to relax isolated rat aorta precontracted with phenylephrine (1 μM) was examined. The compound of Example 46b had an EC ₅₀ value of about 7 μM and was an effective relaxant in rat aorta. The vasorelaxant response elicited by the compound of Example 46b disappeared in the presence of ODQ, a potent and selective inhibitor of nitric oxide (NO) sensitive guanylate cyclase.

Example 88: Angiotensin II-induced contraction in rat aorta Male Wistar rats (250-300 g) were anesthetized with ketamine (10 mg / kg ip) and exsanguinated to remove their abdominal aorta. After removal of fat and connective tissue, the aorta is cut into 3-4 mm lengths and Krebs' modified solution (composition, mM: NaCl 119, CaCl ₂ 2.5, KCl 4.5, NaHCO ₃ 25, MgCl ₂ 1.25, NaHPO ₄ It was suspended in a 10 ml organ bath containing 1.0, D-glucose 11.1). The Krebs' solution was maintained at 37 ° C. and was gassed with 5% CO ₂ in O ₂ . The aortic ring was suspended with an initial static tension of 1.5 g and washed every 15 minutes for a 60 minute equilibration time. After the equilibration time, the aortic ring was contracted with 1 μM phenylephrine. When the contraction for phenylephrine reached a plateau, the tissue was washed 3 times for 15 minutes. Test substance or vehicle (DMSO) was added to the tissue and after 20 minutes each tissue was contracted with angiotensin II (100 nM) and the experiment was terminated after the contraction for angiotensin II had reached its maximum value. Results were calculated as the percentage of maximum contraction caused by 100 nM angiotensin II in tissues receiving only DMSO medium.

  HCT that inhibits contraction induced by 100 nM angiotensin II in the isolated rat aorta, the compound of Example 17b, the compound of Example 51, the compound of Example 56b, and the des-NO of the compound of Example 17b, Example 26 The ability of metabolites was examined. Neither the HCT nor the des-NO compound of Example 26 significantly inhibited angiotensin II-induced contraction, whereas the compound of Example 17b, the compound of Example 51 and the compound of Example 56b did not significantly inhibit. Produced (Table 3). The difference in their activity is likely due to the ability of the compound of Example 17b, Example 51 and Example 56b to release bioavailable NO in the rat aorta.

Example 89: Blood pressure measurement under in vivo conditions in Dahl salt-sensitive rats
Remote measurement of male Dahl salt-sensitive rats (5-6 weeks old; 125-150 g) fed a high salt (8%) diet for 4 weeks affected the blood pressure of the compound of Example 1c and hydrochlorothiazide (HCT) The effect of chronic administration was evaluated. The compound was administered twice a day for 7-8 days by gavage at 0.5 mg methylcellulose medium at 30 mg / kg HCT equivalent. Blood pressure was continuously monitored by telemetry and recorded as changes in mean arterial pressure (MABP) over a 24-hour period.

  Hypertension due to saline (approximately 10 mm Hg change in mean arterial pressure) was observed in vehicle-treated animals during the treatment period. It was shown that animals treated orally twice daily with the compound of Example 1c but not HCT at 30 mg / kg showed a decrease in blood pressure (approximately 5 mm Hg) during the treatment period. It is clear from

Example 90: Measurement of blood pressure under in vivo conditions in spontaneously hypertensive rats Effect of the compound of Example 17b and hydrochlorothiazide on blood pressure in telemetry of male spontaneously hypertensive rats (SHR; 9-10 weeks old; 250-300 g) The effect of subchronic administration of (HCT) was evaluated. The compound was administered twice a day for 7-8 days by gavage at 0.5 mg methylcellulose medium at 30 mg / kg HCT equivalent. Blood pressure was continuously monitored by telemetry and recorded as changes in mean arterial pressure (MABP) over a 24-hour period.

  Animals treated orally with the compound of Example 17b twice daily showed a much lower blood pressure (approximately 5-6 mm Hg) during the treatment period than animals treated with HCT. This is clear from FIG.

  The disclosures of each patent, patent application, and publication cited or described herein are hereby incorporated by reference in their entirety.

  Although the present invention has been described in detail, those skilled in the art can make numerous changes and modifications to the present invention, and such modifications and improvements can be made without departing from the spirit and scope of the present invention. I think you understand that.

Figure 3 shows the blood pressure lowering effect of hydrochlorothiazide and the compound of Example 1b in Dahl salt-sensitive rats. Figure 3 shows the blood pressure lowering effect of hydrochlorothiazide and the compound of Example 17b in spontaneously hypertensive rats.

Claims (24)

A compound of formula (I), or a pharmaceutically acceptable salt thereof, which is:

Where:
X ₂ is -C (O)-or -S (O) ₂ ;
Y ₂ is chlorine or CF ₃ ;
-V ₂ -U ₂ -W _2- is:
(i) -NH- (C (R _q ) (R _r ))-NR _q- ; or
(ii) -NH-C (R _q ) = N-;
R _q and R _r each independently represent hydrogen, a lower alkyl group, a substituted alkyl group, a benzyl group, an aryl group, an alkylaryl group, —CH ₂ —S—CH—CH═CH ₂ ; —CH ₂ — S-CF ₃ , -CH ₂ -S-CH ₂ -C ₆ H ₅ or K ';
K 'is -GE _c- (C (R _e ) (R _f )) _x -W _d- (C (R _e ) (R _f )) _y -W _i -E _j -W _g- (C (R _e ) (R _f )) _z -V ₄ ;
K is-(W) _a -E _b- (C (R _e ) (R _f )) _p1 -E _c- (C (R _e ) (R _f )) _x- (W) _d- (C (R _e ) (R _f )) _y- (W) _i -E _j- (W) _g- (C (R _e ) (R _f )) _z -V ₄ ;
a, b, c, d, g, i and j are each independently an integer from 0 to 3;
p ₁ , x, y and z are each independently an integer from 0 to 10;
G is a heterocyclic, -CH _2, oxygen or nitrogen;
V ₄ is V ₃ , R _e , -U ₃ -V ₅ or V ₆ ;
V ₃ is the following:

R ₂₄ is -C ₆ H ₄ R ₂₉ , -CN, -S (O) ₂ -C ₆ H ₄ R ₂₉ , -C (O) -N (R _a ) (R _i ), -NO ₂ , -C (O) -OR ₂₅ or -S (O) ₂ -R ₂₅ ;
R ₂₅ is an aryl group, a lower alkyl group, a haloalkyl group, a hydroxyalkyl group or an arylalkyl group;
R ₂₆ is -C (O)-or -S (O) _2- ;
R ₂₉ is hydrogen, -CN, -S (O) ₂ -R ₂₅ , -C (O) -N (R _a ) (R _i ), -NO ₂ or -C (O) -OR ₂₅ ;
T ′ is oxygen, sulfur or NR ₆ ;
R ₆ is hydrogen, a lower alkyl group, or an aryl group;
V ₆ is the following:

Z ₅ is -CH ₂ or oxygen;
Z ₆ is -CH or nitrogen;
k ₁ is an integer from 1 to 3;
At each occurrence of W, -C (O)-, -C (S)-, -T ₃ -,-(C (R _e) (R _f )) _h- , -N (R _a ) R _i, alkyl group, aryl group, heterocyclic, aryl _{heterocyclic, - (CH 2 CH 2 O} ) q1 - or be a heterocyclic nitric oxide donor;
Each occurrence of E is independently -T _3- , alkyl group, aryl group,-(C (R _e ) (R _f )) _h- , heterocycle, arylheterocycle,-(CH ₂ CH ₂ O) _ql -or Y ₄ ;
Y ₄ is:

T is -S (O) _o- ; carbonyl or covalent bond;
o is an integer from 0 to 2;
R _j and R _k are independently selected from alkyl groups, aryl groups, or R _j and R _k together with the nitrogen atom to which they are attached are heterocycles;
T ₃ is independently a covalent bond, carbonyl, oxygen, —S (O) _o — or —N (R _a ) R _i at each occurrence;
h is an integer from 1 to 10;
q ₁ is an integer from 1 to 5;
R _e and R _f are each independently hydrogen, alkyl, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, arylheterocycle, alkylaryl, alkylcycloalkyl, alkylheterocycle, cycloalkylalkyl, cycloalkylthio, aryl Alkylthio, arylalkylthioalkyl, alkylthioalkyl, cycloalkenyl, heterocyclic alkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, sulfonic acid, sulfonate ester, alkyl Sulfonic acid, arylsulfonic acid, arylalkoxy, alkylthio, arylthio, cyano, aminoalkyl, aminoaryl, ali , Arylalkyl, alkylaryl, carboxamide, alkylcarboxamide, arylcarboxamide, amidyl, carboxyl, carbamoyl, alkylcarboxylic acid, arylcarboxylic acid, alkylcarbonyl, arylcarbonyl, ester, carboxylic acid ester, alkylcarboxylic acid ester, arylcarboxylic acid Ester, sulfonamide, alkylsulfonamide, arylsulfonamide, alkylsulfonyl, alkylsulfonyloxy, arylsulfonyl, arylsulfonyloxy, sulfonic acid ester, alkyl ester, aryl ester, urea, phosphoryl, nitro, -U ₃ -V ₅ , V ₆ ,-(C (R _o ) (R _p )) _k1 -U ₃ -V ₅ ,-(C (R _o ) (R _p )) _k1 -U ₃ -V ₃ ,-(C (R _o ) _{(R p)) k1 -U 3} -V 6, - (C (R o) (R p)) is a _{k1 -U 3 -C (O) -V} 6, or binding Carbonyl R _e and R _f taken together with the carbon to which it has to have, Methanthial, heterocycle, cycloalkyl group, aryl group, oxime, imine, hydrazone, a bridged cycloalkyl group,

Forming;
R _O and R _P are each independently hydrogen, alkyl, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, arylheterocycle, alkylaryl, alkylcycloalkyl, alkylheterocycle, cycloalkylalkyl, cycloalkylthio, aryl Alkylthio, arylalkylthioalkyl, alkylthioalkyl, cycloalkenyl, heterocyclic alkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, sulfonic acid, sulfonate ester, alkyl Sulfonic acid, arylsulfonic acid, arylalkoxy, alkylthio, arylthio, cyano, aminoalkyl, aminoaryl, ali , Arylalkyl, alkylaryl, carboxamide, alkylcarboxamide, arylcarboxamide, amidyl, carboxyl, carbamoyl, alkylcarboxylic acid, arylcarboxylic acid, alkylcarbonyl, arylcarbonyl, ester, carboxylic acid ester, alkylcarboxylic acid ester, arylcarboxylic acid Ester, sulfonamide, alkylsulfonamide, arylsulfonamide, alkylsulfonyl, alkylsulfonyloxy, arylsulfonyl, arylsulfonyloxy, sulfonic acid ester, alkyl ester, aryl ester, urea, phosphoryl, nitro, -U ₃ -V ₅ , a V _6, or combine with R _O and R _P taken together with the carbon which is a carbonyl, Methanthial, heterocycle, cycloalkyl group, Aryl group, oxime, imine, hydrazone, a bridged cycloalkyl group,

Forming;
U ₃ is oxygen, sulfur or -N (R _a ) R _i ;
V ₅ is -NO or -NO ₂ (i.e. nitric oxide);
k _l is an integer from 1 to 3;
R _a is a lone pair, hydrogen or an alkyl group;
R _i is hydrogen, alkyl, aryl, alkylcarboxylic acid, arylcarboxylic acid, alkylcarboxylic acid ester, arylcarboxylic acid ester, alkylcarboxamide, arylcarboxamide, alkylaryl, alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy, arylsulfinyl, aryl sulfonyl, arylsulfonyloxy, sulfonamido, carboxamido, carboxylic acid esters, aminoalkyl, _{aminoaryl, -CH 2 -C- (U 3 -V} 5) (R e) (R f), there a bond with an adjacent atom A bond that provides a double bond to the atom or M ₁ ⁺ is an organic or inorganic cation — (N ₂ O ₂ —) · M ₁ ⁺ ; and the compound of formula (I) is an —ONO group , -SnO group, -nno group, -ONO ₂ group, -SnO ₂ group, -nno _{2 group, - (N 2 O 2 -} ) · M 1 + group, nitric oxide donating heterocyclic At least one nitric oxide enhancing group selected from a group and a nitroxide group, comprising a nitric oxide enhancing group attached to a compound of formula (I) by a carbon, oxygen and / or nitrogen atom via a non-hydrolyzable bond It is a condition that it must be.   A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.   Compounds of formula (I) are nitric oxide enhanced althiazide, nitric oxide enhanced bendroflumethiazide, nitric oxide enhanced benzthiazide, nitric oxide enhanced butiazide, nitric oxide enhanced chlorothiazide, nitric oxide enhanced cyclothiazide, nitric oxide enhanced ethiazide, nitric oxide Enhanced fenxone, nitric oxide enhanced hydrochlorothiazide, nitric oxide enhanced hydroflumethiazide, nitric oxide enhanced methycrothiazide, nitric oxide enhanced metrazone, nitric oxide enhanced paraflutidide, nitric oxide enhanced polythiazide, nitric oxide enhanced kinetazone, nitric oxide enhanced tecrothiazide, nitric oxide enhanced trichlor 2. The compound of claim 1, which is methiazide, or a pharmaceutically acceptable salt thereof. The compound of formula (I) is a compound of formula (II) to formula (XXVII), or a pharmaceutically acceptable salt thereof,
The compound of claim 3, wherein the compounds of formula (II) to formula (XXVII) are:

Y ₂ is chlorine or CF ₃ ;
x ₁ is an integer from 1 to 6;
y ₁ is an integer from 0 to 3;
R ₃₀ is hydrogen, a lower alkyl group, — (CH ₂ ) _x1 —O—NO ₂ ; and
R ₃₁ is hydrogen or a lower alkyl group.   A method of treating a condition resulting from overhydration and / or electrolyte retention in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the composition of claim 2.   The condition resulting from overhydration and / or electrolyte retention is swollen leg, fatigue, fluid retention, cardiac hypertrophy, lung edema, brain edema, at least partially heart failure, cirrhosis, poor circulation, lymphatic system disorder, chronic nephritis, malnutrition Is the result of oral contraceptive use, premenstrual syndrome, sunburn, hypertension, Meniere's disease, glaucoma, cystic fibrosis and / or edema related to factors selected from the group consisting of sodium and potassium imbalance 6. The method according to claim 5.   A method of treating cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the composition of claim 2.   Cardiovascular disease is heart failure, restenosis, hypertension, diastolic dysfunction, coronary artery disease, myocardial infarction, cerebral infarction, atherosclerosis, atherogenesis, cerebrovascular disease, angina, aneurysm, ischemic heart disease, cerebral imagination Blood, myocardial ischemia, thrombosis, platelet aggregation, platelet adhesion, smooth muscle cell proliferation, vascular or non-vascular complications associated with the use of medical devices, wounds associated with the use of medical devices, blood vessels or non-vascular walls Injury, peripheral vascular disease, neointimal hyperplasia after percutaneous transluminal coronary angiography, blood vessel transplantation, coronary artery bypass surgery, thromboembolic event, stenosis after angioplasty, coronary plaque inflammation, hypercholesterolemia, embolism 8. The method of claim 7, wherein the disease is stroke, stroke, shock, arrhythmia, atrial fibrillation or flutter, or thromboocclusive and reocclusive cerebrovascular incident.   9. The method of claim 8, wherein the cardiovascular disease is hypertension, heart failure or diastolic dysfunction.   A method of treating a renovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the composition of claim 2.   11. The method according to claim 10, wherein the renovascular disease is renal failure, renal dysfunction, renal alteration associated with severe hypertension or renovascular hypertension.   Treating a disease resulting from oxidative stress in a patient in need thereof; treating endothelial dysfunction; comprising administering a therapeutically effective amount of the composition of claim 2 to the patient; caused by endothelial dysfunction Treat disease; treat cirrhosis; treat preeclampsia; treat osteoporosis; treat nephropathy; treat peripheral vascular disease; treat portal hypertension; treat central nervous system disorder To treat metabolic syndrome; to treat sexual dysfunction or to treat hyperlipidemia.   3. The composition of claim 2, further comprising (i) at least one therapeutic agent; (ii) at least one nitric oxide enhancing compound; or (iii) at least one therapeutic agent and at least one nitric oxide enhancing compound. Therapeutic agents are aldosterone antagonists, α-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin converting enzyme inhibitors, antidiabetic compounds, antihyperlipidemic compounds, antioxidants, antithrombotic and vasodilatory compounds, β - adrenergic antagonists, calcium channel blockers, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H ₂ receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds, phosphodiesterase inhibitors, potassium channel blockers 14. The composition of claim 13, wherein the composition is a platelet reducing agent, a proton pump inhibitor, a renin inhibitor, a selective cyclooxygenase-2 inhibitor, or a combination of two or more thereof.   The therapeutic agent is at least one compound selected from the group consisting of aldosterone antagonists, angiotensin II antagonists, angiotensin converting enzyme inhibitors, β-adrenergic antagonists, potassium channel blockers, diuretics, hydralazine compounds and renin inhibitors. 15. A composition according to claim 14.   The aldosterone antagonist is eplerenone or spironolactone; the angiotensin II antagonist is candesartan cilexetil, eprosartan mesylate, irbesartan, losartan potassium, medoxomil, telmisartan, trandolapril, trandolaprilat or valsartan; angiotensin converting enzyme inhibitor Is benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril hydrochloride, quinapril hydrochloride, ramipril; β-adrenergic antagonists are bisoprolol fumarate, carvedilol, metoprolol tartrate, timolol roll tartrate, or timolol maleate ; Calcium channel blocker is amlodipine, diltiase , Isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine or verapamil; the diuretic is amiloride hydrochloride, chlorthalidone, hydrochlorothiazide or triamterene; the hydralazine compound is hydralazine hydrochloride; and the renin inhibitor is aliskiren, cyproxylene, 16. A composition according to claim 15, which is enalkrein, medullipin, remiquiren, terlkiren, tonin or zankyrene.   Nitric oxide enhancing compounds are S-nitrosothiol, nitrite, nitrate, S-nitrothiol, sydnonimine, NONOate (NONOate), N-nitrosamine, N-hydroxyl nitrosamine, nitrosimine, diazetin dioxide, 14. The composition of claim 13, selected from the group consisting of oxatriazole 5-imine, oxime, hydroxylamine, N-hydroxyguanidine compound, hydroxyurea, furoxan or nitroxide.   further comprising: (i) at least one therapeutic agent; (ii) at least one nitric oxide enhancing compound, (iii) at least one therapeutic agent and at least one nitric oxide enhancing compound. The method according to 10 or 12. Therapeutic agents are aldosterone antagonists, α-adrenergic receptor agonists, α-adrenergic receptor antagonists, angiotensin II antagonists, angiotensin converting enzyme inhibitors, antidiabetic compounds, antihyperlipidemic compounds, antibacterial compounds, antioxidants, Antithrombotic and vasodilatory compounds, β-adrenergic antagonists, calcium channel blockers, carbonic anhydrase inhibitors, digitalis, diuretics, endothelin antagonists, hydralazine compounds, H ₂ receptor antagonists, neutral endopeptidase inhibition Agent, non-steroidal anti-inflammatory compound, phosphodiesterase inhibitor, potassium channel blocker, thrombocytopenia, prostaglandin, proton pump inhibitor, renin inhibitor, selective cyclooxygenase-2 Harm agent, a steroid, or two or more combinations thereof, The method of claim 18, wherein.   Nitric oxide donor compounds are S-nitrosothiol, nitrite, nitrate, S-nitrothiol, sydnonimine, NONOate, N-nitrosamine, N-hydroxylnitrosamine, nitrosimine, diazetin dioxide, oxatriazole 5-imine, oxime, hydroxylamine, 19. The method of claim 18, wherein the method is selected from the group consisting of an N-hydroxyguanidine compound, hydroxyurea, furoxan or nitroxide.   A kit comprising at least one compound according to claim 1.   24. The kit of claim 21, further comprising (i) at least one therapeutic agent; (ii) at least one nitric oxide enhancing compound; or (iii) at least one therapeutic agent and at least one nitric oxide enhancing compound.   (i) at least one therapeutic agent; (ii) at least one nitric oxide enhancing compound; or (iii) at least one therapeutic agent and at least one nitric oxide enhancing compound are present in the form of separate components in the kit, The kit according to claim 22. A compound selected from the group consisting of:
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [5- (nitrooxy) pentyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- [3,4-bis (nitrooxy) butyl] -6-chloro-3,4-dihydro-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [3- (nitrooxy) propyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- (4-methyl-5-oxide-1,2,5-oxadiazole-3 -Yl)-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide, (3R)- ;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide, (3S)- ;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6-chloro-1 '-[5- (nitrooxy) -1-oxopentyl] -, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[4,5-bis (nitrooxy) -1-oxopentyl]- 6-chloro-, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6-chloro-1 '-[2-methyl-3- (nitrooxy) -2 -[(Nitrooxy) methyl] -1-oxopropyl]-, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6-chloro-1 '-[3-[(nitrooxy) methyl] benzoyl]- , 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 6-chloro-1 '-[6- (nitrooxy) -1-oxohexyl] -, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-2-acetic acid, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-, (2R) -2,3-bis (nitrooxy) propyl ester, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2-[[3-[(nitrooxy) methyl] phenyl] methyl]-, 1,1- Dioxide;
2H-1,2,4-Benzothiadiazine-2-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N- [3- (nitrooxy) propyl]-, 1,1- Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [3- (nitrooxy) propyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[[4- [2- (nitrooxy) ethyl] -1-piperidinyl] methyl]- , 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[[4- [2- (nitrooxy) ethyl] -1-piperidinyl] methyl]- , 1,1-dioxide, 2-hydroxy-1,2,3-propanetricarboxylate (1: 1) (salt);
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2-[(4-methyl-5-oxide-1,2,5-oxadiazole- 3-yl) methyl]-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-2-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N-methyl-N- [2- (nitrooxy) ethyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-2-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N, N-bis [2- (nitrooxy) ethyl]-, 1 , 1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [4- (nitrooxy) butyl]-, 1,1-dioxide;
Pentanoic acid, 4,5-bis (nitrooxy)-, 2- [7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadia Gin-2-yl] ethyl ester;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [4,5-bis (nitrooxy) pentyl] -6-chloro-3,4-dihydro-, 1,1-dioxide;
Pentanoic acid, 5- (nitrooxy)-, 2- [7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazine-2 -Yl] ethyl ester;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[[methyl [2- (nitrooxy) ethyl] amino] methyl]-, 1,1 -Dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [5- (nitrooxy) pentyl]-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [6- (nitrooxy) hexyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[(3S) -3,4-bis (nitrooxy) butyl] -6-chloro-3,4-dihydro-, 1,1 -Dioxide;
2H-1,2,4-Benzothiadiazine-3-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N, N-bis [2- (nitrooxy) ethyl]-, 1 , 1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- [3,5-bis [(nitrooxy) methyl] phenyl] -6-chloro-3,4-dihydro-, 1,1- Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [2- (nitrooxy) ethyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-4-nitro-2- [2- (nitrooxy) ethyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [4- (nitrooxy) -3,3-bis [(nitrooxy) methyl] butyl] -, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [5- (nitrooxy) -4,4-bis [(nitrooxy) methyl] pentyl] -, 1,1-dioxide;
Acetamide, N-[[7- (Aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] methyl] -2 -[Bis [2- (nitrooxy) ethyl] amino]-;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [6- (nitrooxy) hexyl]-, 1,1-dioxide;
Acetamide, N-[[7- (Aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] methyl] -2 -[Bis [2- (nitrooxy) ethyl] amino] -N-methyl-;
(5-{[{[7- (Aminosulfonyl) -6-chloro-1,1-dioxide-3,4-dihydro-2H-1,2,4-benzothiadiazin-3-yl] methyl} ( Methyl) amino] carbonyl} -1,3-phenylene) bis (methylene) dinitrate;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2-[(2E) -4- (nitrooxy) -2-butenyl], 1,1- Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[[3- (4-Bromobutoxy) -5-[(nitrooxy) methyl] phenyl] methyl] -6-chloro-3, 4-dihydro-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [4- [3,5-bis [(nitrooxy) methyl] phenoxy] butyl] -6-chloro-3,4-dihydro- , 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [3- [3,5-bis [(nitrooxy) methyl] phenoxy] propyl] -6-chloro-3,4-dihydro- , 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [2- [3,5-bis [(nitrooxy) methyl] phenoxy] ethyl] -6-chloro-3,4-dihydro- , 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-2-acetamide, 7- (aminosulfonyl) -6-chloro-3,4-dihydro-N, N-bis [3- (nitrooxy) propyl]-, 1 , 1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[(3R) -3,4-bis (nitrooxy) butyl] -6-chloro-3,4-dihydro-, 1,1 -Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3- [2- (nitrooxy) ethyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[(2R) -2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-, 1,1 -Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2-[(2S) -2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-, 1,1 -Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 2- [2,3-bis (nitrooxy) propyl] -6-chloro-3,4-dihydro-4-nitro-, 1,1 -Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [2-hydroxy-3- (nitrooxy) propyl] -4-nitro-, 1, 1-dioxide;
1-piperidinyloxy, 4-[[7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl ] Methyl] -2,2,6,6-tetramethyl-;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-3-[(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl ) Methyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- [2- [3,5-bis [(nitrooxy) methyl] phenyl] ethyl] -6-chloro-3,4-dihydro- , 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-4-methyl-3- [4- (nitrooxy) butyl]-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3-[(1R) -1,2-bis (nitrooxy) ethyl] -6-chloro-3,4-dihydro-4-methyl- , 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3-[(1S) -1,2-bis (nitrooxy) ethyl] -6-chloro-3,4-dihydro-4-methyl- , 1,1-dioxide;
1-pyrrolidinyloxy, 3- [7- (aminosulfonyl) -6-chloro-3,4-dihydro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] -2,2,5,5-tetramethyl-;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -1'-yloxy, 7- (aminosulfonyl) -6-chloro-2 ', 2', 6 ' , 6'-tetramethyl-1,1-dioxide-;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-2- [3- (nitrooxy) -2-[(nitrooxy) methyl] propyl]-, 1 , 1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- [5- (nitrooxy) pentyl] -6- (trifluoromethyl)-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- [3- (nitrooxy) propyl] -6- (trifluoromethyl)-, 1,1-dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3- [3,4-bis (nitrooxy) butyl] -3,4-dihydro-6- (trifluoromethyl)-, 1,1 -Dioxide;
2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- (4-methyl-5-oxide-1,2,5-oxadiazol-3-yl)- 6- (trifluoromethyl)-, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[5- (nitrooxy) -1-oxopentyl] -6- ( (Trifluoromethyl)-, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[3-[(nitrooxy) methyl] benzoyl] -6- (tri Fluoromethyl)-, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[2-methyl-3- (nitrooxy) -2-[(nitrooxy ) Methyl] -1-oxopropyl] -6- (trifluoromethyl)-, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[2,2-dimethyl-3- (nitrooxy) -1-oxo Propyl] -6- (trifluoromethyl)-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 3- [3,5-bis [(nitrooxy) methyl] phenyl] -3,4-dihydro-6- (trifluoromethyl)-, 1,1-dioxide;
2H-1,2,4-benzothiadiazine-7-sulfonamide, 3,4-dihydro-3- [4- (nitrooxy) butyl] -6- (trifluoromethyl)-, 1,1-dioxide;
Spiro [2H-1,2,4-benzothiadiazine-3 (4H), 4'-piperidine] -7-sulfonamide, 1 '-[6 (nitrooxy) -1-oxohexyl] -6- (tri Fluoromethyl)-, 1,1-dioxide;
Pentanamide, N- [7- (aminosulfonyl) -6-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] -5- (nitrooxy)-;
Hexanamide, N- [7- (aminosulfonyl) -6-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl] -6- (nitrooxy)-;
4H-1,2,4-Benzothiadiazine-3-butanamide, 7- (aminosulfonyl) -N-[(2R) -2,3-bis (nitrooxy) propyl] -6-chloro-, 1,1 -Dioxide;
4H-1,2,4-Benzothiadiazine-3-propanamide, 7- (aminosulfonyl) -6-chloro-N- [2- [2- (nitrooxy) ethoxy] ethyl]-, 1,1- Dioxide;
4H-1,2,4-benzothiadiazine-3-butanamide, 7- (aminosulfonyl) -6-chloro-N- [2- (nitrooxy) ethyl]-, 1,1-dioxide;
4H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3- [5- (nitrooxy) pentyl]-, 1,1-dioxide;
4H-1,2,4-Benzothiadiazine-3-butanamide, 7- (aminosulfonyl) -N-[(2S) -2,3-bis (nitrooxy) propyl] -6-chloro-, 1,1 -Dioxide;
4H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3- [4- (nitrooxy) butyl]-, 1,1-dioxide;
N- (5-chloro-2,4-disulfamoylphenyl) -2- {4-[(nitrooxy) methyl] phenyl} acetamide;
4H-1,2,4-benzothiadiazine-7-sulfonamide, 6-chloro-3-[[4-[(nitrooxy) methyl] phenyl] methyl]-, 1,1-dioxide; and pharmaceutically Its acceptable salt.

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